ICR 11.2 by Radcliffe Cardiology

Volume 11 • Issue 2 • Winter 2016

www.ICRjournal.com

Percutaneous Coronary Intervention in Older People: Does Age Make a Difference? Sami A Omar and Adam de Belder

Preventing Contrast-induced Renal Failure: A Guide Michela Faggioni and Roxana Mehran

Drug-coated Balloon-only Angioplasty for Native Coronary Disease Instead of Stents Upul Wickramarachchi and Simon Eccleshall

The Changing Paradigm in the Treatment of Structural Heart Disease and the Need for the Interventional Imaging Specialist Nina C Wunderlich, Harald Küx, Felix Kreidel, Ralf Birkemeyer and Robert J Siegel

(B)

A2 Apex→

5 Coronary CT angiography-derived FFR

6 Cardiac magnetic resonance imaging

Lipid differentiation map overlaid on intravascular ←Mitral valve level ultrasound

Late enhancement

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

Lengths ahead in diabetic patient outcomes UNIQUE

BETTER

LONGER

UNIQUE

BETTER

Polymer-free

The RESERVOIR clinical trial: independent randomized comparison of Cre8TM vs Xience® in patients with Diabetes Mellitus*

CMY

• Abluminal Reservoir

Technology

Cre8TM 56 pts

• Amphilimus

formulation Sirolimus + Organic Acid

• Bio-Inducer Surface

coating

0.3

0.24±0.57

0.2

-42%

0.15

0.14±0.24

(mm)

2,50 2,75 3,00 3,50

LATE LUMEN LOSS

25.0

length

* * * *

20.0

Frequency

The images shown within this document are of a purely illustrative nature and are not intended to depict reality

Xience® 56 pts

ANGIOGRAPHIC RESULTS AT 6 MONTHS

0.25

Untitled-1 1

PI Dr. R. Romaguera

Randomization 1:1 TM

DIABETIC PATIENTS

LONGER

15.0

10.0

0.1 5.0

0.05

Cre8TM

In stent

.0 -.50

Xience® .00

.50

1.00

1.50

2.00

2.50

3.00 -.50

.00

.50

1.00

1.50

2.00

2.50

3.00

CRE8TM HIGHLY REDUCES LLL WITH A BETTER RESULT CONSISTENCY Funded by the Spanish Society of Cardiology

*Romaguera et al. JACC: CARDIOVASCULAR INTERVENTIONS VOL.9,NO.1,2016:42–50

Cre8

AMPHILIMUS™ ELUTING CORONARY STENT Manufactured by CID S.p.A. member of Alvimedica Group Strada per Crescentino, sn - 13040 Saluggia (VC), Italy

www.alvimedica.com

Currently not available in US and Japan. Please consult product labels and package inserts for indications, contraindications, hazards, warnings, cautions and instruction for use. ©2016, Alvimedica. All Rights Reserved.

30/09/2016 18:52

Volume 11 • Issue 2 • Winter 2016

www.ICRjournal.com

Editor-in-Chief Simon Kennon Interventional Cardiologist and TAVI Operator, Barts Heart Centre, St Bartholomew’s Hospital, London

Section Editor – Structural

Section Editor – Coronary

Darren Mylotte

Angela Hoye

Galway University Hospitals, Galway

Castle Hill Hospital, Hull

Fernando Alfonso

A Pieter Kappetein

Hospital Universitario de La Princesa, Madrid

Andrew Archbold

Thoraxcenter, Erasmus University Medical Center, Rotterdam

London Chest Hospital, Barts Health NHS Trust, London

Demosthenes Katritsis

Sergio Baptista

Tim Kinnaird

Hospital CUF Cascais and Hospital Fernando Fonseca, Portugal

Marco Barbanti

Athens Euroclinic, Athens, Greece University Hospital of Wales, Cardiff

Ajay Kirtane Columbia University Medical Center and New York-Presbyterian Hospital, New York

Ferrarotto Hospital, Catania

Olivier Bertrand Quebec Heart-Lung Institute, Laval University, Quebec

Azeem Latib

Lutz Buellesfeld

Didier Locca

San Raffaele Hospital, Milan

University Hospital, Bern

Jonathan Byrne King’s College Hospital, London

Antonio Colombo San Raffaele Hospital, Milan

Royal Brompton & Harefield NHS Foundation Trust, London Centre Hospitalier Universitaire Vaudois, Lausanne CardioVascular Center, Frankfurt

Sapienza University of Rome, Rome

Andrew SP Sharp Royal Devon and Exeter Hospital and University of Exeter, Exeter

Elliot Smith London Chest Hospital, Barts Health NHS Trust, London Rigshospitalet - Copenhagen University Hospital, Copenhagen

Thomas Modine

Gregg Stone Columbia University Medical Center and New York-Presbyterian Hospital, New York

Corrado Tamburino Ferrarotto & Policlinico Hospital and University of Catania, Catania

Center for Intensive Internal Medicine, University Medical Center, Ljubljana

Nicolas Van Mieghem

Keith Oldroyd

Renu Virmani

Golden Jubilee National Hospital, Glasgow

Sameer Gafoor

Gennaro Sardella

Mount Sinai Hospital, New York

Marko Noc

Eric Eeckhout

Beth Israel Deaconess Medical Center, Boston

Lars Søndergaard

Columbia University Medical Center and New York-Presbyterian Hospital, New York

Carlo Di Mario

Jeffrey Popma

Roxana Mehran

Jeffrey Moses

Imperial College NHS Trust, London

Guy’s & St Thomas’ Hospital and King’s College London, London

Lausanne University Hospital, Lausanne

CHRU de Lille, Lille

Justin Davies

Divaka Perera

Crochan J O’Sullivan

Erasmus University Medical Center, Rotterdam CVPath Institute, Maryland

Mark Westwood

Triemli Hospital, Zurich

London Chest Hospital, Barts Health NHS Trust, London

Thomas Johnson

Nicolo Piazza

Nina C Wunderlich

University Hospitals Bristol, Bristol

McGill University Health Center, Montreal

Cardiovascular Center Darmstadt, Darmstadt

Juan Granada CRF Skirball Research Center, New York

Managing Editor Lindsey Mathews • Production Jennifer Lucy Digital Commercial Manager Ben Sullivan • New Business & Partnership Director Rob Barclay Publishing Director Liam O’Neill • Managing Director David Ramsey • Commercial Director Mark Watson •

Editorial Contact Lindsey Mathews commeditor@radcliffecardiology.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com Cover image

•

Human heart for medical study © angelhell | istockphoto.com

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire, SL8 5AS © 2016 All rights reserved

Radcliffe Cardiology

ISSN: 1756–1477 • eISSN: 1756–1485

ICR11.2_MH.indd 81

30/09/2016 19:20

Established: June 2006 Frequency: Bi-annual Current issue: Winter 2016

Aims and Scope • Interventional Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in interventional cardiology practice. • Interventional Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • Interventional Cardiology Review provides comprehensive updates on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

Structure and Format • •

• •

Interventional Cardiology Review is a bi-annual journal comprising review articles, expert opinion articles and guest editorials. The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Section Editors and Editorial Board. Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. Each edition of Interventional Cardiology Review is available in full online at www.ICRjournal.com

•

Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is assessed to ensure the revised version meets quality expectations. The manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Submissions and Instructions to Authors •

•

• •

Contributors are identified by the Editor-in-Chief with the support of the Section Editors and Managing Editor, and guidance from the Editorial Board. Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief and Section Editors, formalise the working title and scope of the article. The ‘Instructions to Authors’ document and additional submission details are available at www.ICRjournal.com Leading authorities wishing to discuss potential submissions should contact the Managing Editor, Lindsey Mathews commeditor@radcliffecardiology.com

Reprints All articles included in Interventional Cardiology Review are available as reprints. Please contact the Publishing Director, Liam O’Neill liam.oneill@radcliffecardiology.com

Editorial Expertise

Distribution and Readership

Interventional Cardiology Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by Section Editors and an Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors who are recognised authorities in their respective fields. • Peer review – conducted by experts appointed for their experience and knowledge of a specific topic. • An experienced team of Editors and Technical Editors.

Interventional Cardiology Review is distributed bi-annually through controlled circulation to senior healthcare professionals in the field in Europe.

Peer Review

All manuscripts published in Interventional Cardiology Review are available free-to-view at www.ICRjournal.com. Also available at www.radcliffecardiology.com are manuscripts from other journals within Radcliffe Cardiology’s cardiovascular portfolio – including, Arrhythmia and Electrophysiology Review, Cardiac Failure Review, European Cardiology Review and US Cardiology Review. n

• •

•

On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion. The Managing Editor, following consultation with the Editor-in-Chief, Section Editors and/or a member of the Editorial Board, sends the manuscript to reviewers who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind. Following review, manuscripts are accepted without modification, accepted pending modification (in which case the manuscripts are returned to the author(s) to incorporate required changes), or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments.

Copyright and Permission Radcliffe Cardiology is the sole owner of all articles and other materials that appear in Interventional Cardiology Review unless otherwise stated. Permission to reproduce an article, either in full or in part, should be sought from the publication’s Managing Editor.

Online

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

ICR_11.1.indd 82

30/09/2016 19:15

Untitled-1 1 d7936 - PUB ESC 2017 - ESC 365-A4-v2-ok.indd 1

30/09/2016 18:54 10/08/2016 10:14

Contents

Foreword 86

Simon Kennon Editor-in-Chief, ICR

Coronary 88

Transradial Approach in Primary Percutaneous Coronary Intervention: Lessons from a High-volume Centre Lieuwe H Piers, Maarten A Vink and Giovanni Amoroso

Expert Opinion Percutaneous Coronary Intervention in Older People: Does Age Make a Difference? Sami A Omar and Adam de Belder

Preventing Contrast-induced Renal Failure: A Guide

1 05

Fractional Flow Reserve Measurement by Computed Tomography: An Alternative to the Stress Test

Michela Faggioni and Roxana Mehran

Ji Hyun Lee, Bríain ó Hartaigh, Donghee Han, Asim Rizvi, Fay Y Lin and James K Min

1 10

Drug-coated Balloon-only Angioplasty for Native Coronary Disease Instead of Stents

1 16

The FAME Trials: Impact on Clinical Decision Making

1 20

Emerging Technology Update Intravascular Photoacoustic Imaging of Vulnerable Atherosclerotic Plaque

Upul Wickramarachchi and Simon Eccleshall

Guy R Heyndrickx and Gábor G Tóth

Min Wu, Antonius FW van der Steen,Evelyn Regar and Gijs van Soest

1 24

The Need For Dedicated Bifurcation Stents: A Critical Analysis Maciej Lesiak

Peripheral 1 28

Non-coronary Interventions: An Introduction to Peripheral Arterial Interventions Brock Cookman, Suhail Allaqaband and Tonga Nfor

Structural 1 35

ICR_contents_11.2.indd 84

01/10/2016 16:30

Untitled-1 85

30/09/2016 18:59

Foreword

Simon Kennon is an Interventional Cardiologist and TAVI Operator at the Barts Heart Centre, St Bartholomew’s Hospital, London. He trained at Manchester University, St Bartholomew’s Hospital, the London Chest Hospital and St Vincent’s Hospital, Melbourne. His research interests relate to aortic valve and coronary interventions.

his year’s two major European interventional cardiology conferences have highlighted the different stages of development of three different aspects of interventional cardiology.

Coronary intervention is a mature subspeciality and presentations at the EuroPCR meeting (Paris, 17–20 May 2016) focussed on highly complex (chronic total occlusions) and high-risk (ST-elevation myocardial infarction) interventions as well as pharmacological and mechanical adjuncts such as antiplatelet agents and support devices for cardiogenic shock. Live cases were of complex interventions and discussion touched on all aspects of the case – reflecting the experience of operators and moderators. Aortic valve intervention is at an intermediate stage of development with presentations at both EuroPCR and PCR London Valves (London, 18–20 September 2016) largely documenting outcomes of first and second generation devices. Live cases were reasonably straight forward with discussion often focussing on device selection and the basics of the procedure. Mitral and tricuspid interventions, however, remain very much in the early stages of development, particularly for the tricuspid valve. At PCR London Valves, Professor Vinayak Bapat (St. Thomas’ Hospital, London) stated that – to his knowledge – no single operator had performed more than 50 transcatheter mitral valve replacement procedures, of any description, in total. This contrasts with aortic valve interventions where most operators will be performing more than this number of procedures annually, and more sharply still with coronary interventions where the highest volume operators will be approaching this number of procedues every month. Presentations concentrated on case selection and hard outcome data where interventions in man have been undertaken. Other presentations related to devices still in development. These are exciting times for valvular interventions but it is important to remember that in many countries there will be individual centres performing more coronary intervention procedures each year than valvular interventions will be performed in the whole country. This issue of Interventional Cardiology Review reflects the overwhelming primacy of coronary artery disease management in the work of the interventional cardiologist and I commend it to you. n

Foreword_ICR 11.2 v03.indd 86

30/09/2016 19:09

LEADERSHIP IN LIVE CASE DEMONSTRATION

F E B R U A R Y 9-11, 2017

JOINT INTERVENTIONAL MEETING IN PARTNERSHIP WITH

, Italy w w w . j i m - v a s c u l a r . c o m ORGANIZING SECRETARIAT Victory Project Congressi • Via C. Poma, 2 - 20129 Milan - Italy Phone +39 02 89 05 35 24 • Fax +39 02 20 13 95 • E-mail info@victoryproject.it JIM_2016.indd 87

30/09/2016 19:00

Coronary

Transradial Approach in Primary Percutaneous Coronary Intervention: Lessons from a High-volume Centre Lieuwe H P i e r s , M a a r t e n A V i n k a n d G i o v a n n i A m o r o s o Department of Cardiology, Onze Lieve Vrouwe Gasthuis (OLVG) Amsterdam, Amsterdam, The Netherlands

Abstract The transradial approach (TRA) is the recommended technique for percutaneous coronary intervention (PCI) in acute coronary syndrome, according to the European Society of Cardiology guidelines. There is a large body of evidence showing reduction in bleeding and mortality when the TRA is used. The TRA is also more convenient for patients, by allowing early mobilisation. Finally, by facilitating patient turnover and fast (re)transfer after the procedure, the TRA enables operators to meet the current recommendations of early invasive therapy in both ST and non-ST-elevation myocardial infarction. On the other hand, the TRA is technically more challenging than the transfemoral approach (TFA) and requires longer learning curve, which hinders its uptake by low-volume operators/centres. Nevertheless, in the hands of experienced high-volume operators, such as at Onze Lieve Vrouwe Gasthuis (OLVG) Amsterdam, the TRA achieves comparable procedural outcomes and favourable clinical results compared with the TFA, as it is in cases of primary PCI.

Keywords Primary percutaneous coronary intervention, percutaneous coronary intervention, transradial, transfemoral, coronary artery disease, ST-elevation myocardial infarction Disclosure: The authors have no conflicts of interest to declare. Received: 13 July 2016 Accepted: 1 September 2016 Citation: Interventional Cardiology Review 2016;11(2):88–92 DOI: 10.15420/icr.2016:21:3 Correspondence: Giovanni Amoroso, Department of Cardiology, OLVG Hospital, Oosterpark 9, 1091 AC Amsterdam, The Netherlands. E: g.amoroso@olvg.nl

The transradial approach (TRA) was introduced for the first time in 1989.1 Used at first by Campeau for coronary angiography, the TRA was later applied by Kiemeneij et al. for percutaneous coronary intervention (PCI).2 The radial artery has proven to be a challenging but safe route towards the coronary arteries. According to the European Society of Cardiology (ESC) guidelines, the radial artery should be the preferred route for percutaneous coronary procedures in acute coronary syndrome (ACS) patients.3 However, the transfemoral approach (TFA) is still used in many centres for primary PCI, mostly in fear of longer door-to-balloon times and worse procedural outcomes.4 In our centre, the TRA represents the first choice treatment in cases of primary PCI. In this review, we will first present the published evidences, then we will share the data and experiences at Onze Lieve Vrouwe Gasthuis (OLVG) Amsterdam, and finally we will discuss the issues of radial artery occlusion and indications for the TFA at a TRA centre.

Transradial Versus Transfemoral Approach in ST-elevation Myocardial Infarction According to both European and North American guidelines, primary PCI is the recommended treatment in patients with ST-elevation myocardial infarction (STEMI), if it can be performed within 2 hours.5,6 Primary PCI provides a higher and faster rate of coronary reperfusion than thrombolysis. Unfortunately, the risk of bleeding complications is not solved. Primary PCI-related bleedings are due to the use of multiple antithrombotic and antiplatelet agents, which is unavoidable to prevent recurrent ischaemic events. The occurrence of a bleeding is not without risk as it is associated with higher mortality.7,8,9 The relationship between bleedings and mortality is often multifactorial,

Access at: www.ICRjournal.com

ICR_Amoroso_FINAL2.indd 88

e.g. haemodynamic compromise, discontinuation of antithrombotic agents and prothrombotic state. Although non-access site bleedings bear a greater relative risk than access site-related bleedings, the latter are also potentially life-threatening. Verheugt et al. showed that, in ACS patients undergoing PCI, an access site bleeding is associated with a twofold increase in 1-year mortality, whereas a non-access site bleeding is associated with a fourfold increase.8 These findings underline the urge not only to refine our therapies (fast on/ off antithrombotics, such as bivalirudin, choice of antiplatelet agents according to bleeding risk score), but also the way interventional procedures should be performed to minimise the risk of bleedings. The first study to compare both femoral, brachial and radial access for PCI was performed by Kiemeneij et al.10 The failure rate of PCI was equal between all groups (8.3, 9.0 and 8.6 %, respectively), and no difference in major adverse cardiac events at 1-month was observed. However, there was a reduction in entry site-related bleeding complications (0.0, 2.3 and 2.0 %, respectively for radial, brachial and femoral access; p=0.035). This pivotal study did not comprise acute patients. The Radial Versus Femoral Access for Coronary Intervention (RIVAL) trial was the first, large-scale multicentre randomised trial comparing the TRA and the TFA in ACS. In this study 7,021 patients undergoing coronary angiography and intervention because of ACS were included.11 The authors detected similar results: no difference in major adverse cardiac events (3.7 and 4.0 %, respectively) but less bleeding in the TRA group (1.9 and 4.5 % Acute Catheterization and Urgent Intervention Triage Strategy [ACUITY] bleeding, respectively)

06/10/2016 23:28

Transradial Approach in Primary Percutaneous Coronary Intervention

and less access site complications (1.4 and 3.7 %, respectively). A sub-analysis of patients with STEMI showed a lower incidence of major adverse cardiac events when the TRA was used compared with the TFA (2.7 and 4.6 %, respectively; p=0.031). Door-to-balloon times were comparable between the TRA and the TFA, as it is confirmed by other studies.12,13 An additional meta-analysis, including all studies comparing the TRA and the TFA PCI in ACS, showed a significant reduction in major bleeding (0.9 versus 1.6 %, respectively), and also a reduced mortality (1.8 versus 2.5 %, respectively), when the TRA was used.14 The Radial Versus Femoral Randomized Investigation in ST-segment Elevation Acute Coronary Syndrome (RIFLE-STEACS) trial, specifically comparing the TRA and the TFA for primary PCI, showed lower mortality with the TRA than the TFA (7.2 versus 9.2 %, respectively; p=0.02).12 The incidence of bleeding, especially access site-related bleeding, was higher in the TFA group. This concomitant reduction corroborates the link between mortality and bleeding. Finally, a recent metaanalysis, pooling 16 randomised studies, showed a relative risk reduction of 33 % in mortality when the TRA is used and 48 % reduction in major bleeding.15 The Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) study is a large trial in which 8,404 ACS patients undergoing PCI were randomised to either the TRA or the TFA. Patients undergoing the TRA had significantly less net adverse clinical events (9.8 %) compared with patients with femoral access (11.7 %). This difference was driven by major bleeding unrelated to coronary artery bypass graft surgery (1.6 versus 2.3 %, respectively for the TRA and the TFA), but also by all-cause mortality (1.6 versus 2.2 %, respectively for the TRA and the TFA).16 A peculiarity of the MATRIX study is that it was conducted by experienced radial operators only.

Transradial Primary Percutaneous Coronary Intervention at Onze Lieve Vrouwe Gasthuis Amsterdam Pre-procedural Logistics OLVG Amsterdam is a large non-academic tertiary referral centre in the centre of Amsterdam, where about 3,000 percutaneous coronary procedures are performed each year, among which about 300 primary PCI and 500 PCI for ACS are performed. The great Amsterdam region consists of an area with 1.4 million inhabitants with three PCI centres and five non-PCI community hospitals. Catchment areas, with active back-up between hospitals, are defined according to postal codes. Patients are directly referred by the ambulance team to the catheter laboratory of the appropriate PCI centre, after teleconsultation (including electrocardiogram). If the patient is accepted for primary PCI, he/she will receive an upload dose of antiplatelets and antithrombotics (Ascal® 160 mg, Ticagrelor 180 mg and Heparin 5,000 UI) in the ambulance. In particular, the choice for Ticagrelor, instead of other P2Y12 inhibitors (Clopidogrel, Prasugrel), has been based both on its efficacy and safety profile in cases of primary PCI and on its broad spectrum of use in ACS patients.17 Thanks to our system, which bypasses both community hospitals and the emergency department, first medical contact-to-balloon time is short – around 82 minutes (interquartile range 70–98).18

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Amoroso_FINAL2.indd 89

Procedural Results At OLVG Amsterdam, the TRA is the standard access site for primary PCI. This is our first treatment choice due to the expectation that clinical outcomes would be better, and to speed up patient turn-over as well as allow faster PCI access to more patients. Vink et al. reported on the procedural outcomes of the TRA primary PCI in our institution between the years 2001 and 2008.19 In this timeframe, 2,484 primary PCI were performed, of which 184 procedures were excluded from analysis because of cardiogenic shock. In the remaining 2,300 cases, the TFA was chosen by the operator in 91 cases (3.9 %), mainly because of recent TRA (19.7 %) or anatomic impediments (18.6 %). Crossover occurred in 3.8 %, mainly because of the inability to reach the coronary ostium (35.7 %) or due to inadequate support of the guiding catheter (16.7 %). Over the years, the need for crossover decreased from 5.9 % to 1.5 %. Procedural success remained stable over time, around 94 %, while procedural times decreased from 38 to 24 minutes. These findings can be attributed to better patient selection, improved materials (in particular puncture kits), but also growing operator experience. These results were also found in the RIVAL trial, where crossover was lower in high-volume centres (4.4 %).11 Indeed, even for OLVG operators, who according to the RIVAL trial definition (>146 cases using the TRA per year) would be defined throughout the years as high-volume operators, there is a continuous margin for improvement, which highlights the technical challenges of the TRA. As a result of the small diameter and anatomic variations of the radial artery, the TRA is more demanding than the TFA. Therefore, the TRA requires a longer learning curve for the operator.20 More experienced operators have lower procedure times, equalling or outperforming the TFA.21 The same applies to radiation exposure.22 Overall, fluoroscopy time is longer and radiation burden is higher with the TRA, except in TRA experienced operators. Also, in our experience radiation exposure is not higher for radial versus femoral procedures, but it is for fellow versus staff interventional cardiologists. To evaluate the impact of a systematic TRA in primary PCI on clinical outcomes, we performed a retrospective analysis of all the primary PCIs of 2015 (unpublished data). The study cohort consisted of 194 patients, directly admitted to the catheter laboratory from the ambulance service, with exclusion of self-referrals to the emergency department and cardiogenic shock.18 The TFA was used in only 3.6 % of patients. No serious bleeding events occurred. The in-hospital mortality was 5.7 % and cumulative 30-day mortality was 6.2 %, which is somewhat worse than results from highly selected randomised studies, such as the Administration of Ticagrelor in the Cath Lab or in the Ambulance for New St-elevation Myocardial Infarction to Open the Coronary Artery (ATLANTIC) study, but comparable to other STEMI reports.12,23 The median door-to-needle time was 21 minutes (interquartile range 14–38) and the median door-to-balloon time was 39 minutes (interquartile range 27–60). This is within the set limit of 60 minutes.3 Based on the published studies and our own experience we are convinced that the TRA guarantees excellent procedural outcomes in cases of primary PCI as well as favourable clinical results. These data collectively suggest the need for the routine use of the TRA percutaneous coronary procedures, as procedure success increases with the experience of the operator, resulting in less catheter manipulation and exchange, and reduces radial artery spasm.

06/10/2016 23:28

Coronary Technical Considerations Procedural techniques for engaging the coronary arteries and performing interventions can vary according to the operator’s preferences and experience. Despite the fact that the right subclavian and brachiocephalic arteries will present slightly more abnormalities than the left ones, all operators at OLVG Amsterdam choose the right radial artery as first access (96 % of primary PCI procedures). This is mostly due to the table set-up and operator’s comfort. When the left radial artery is punctured (i.e. either the right radial is not feasible, or a need to film the left mammary artery), the operator will puncture from the left side of the patient and then the arm will be bent on the abdomen of the patient to be able to continue the procedure from the right side of the table. In our experience, there is no significant difference in procedural and clinical outcomes for primary PCIs performed either from the right or left side. There is some agreement that a single catheter strategy will prevent manipulation and radial spasm and is therefore pursued in most of the primary PCI procedures, by using curves which are suitable for both left and right ostia (Multipurpose, Radial, Kimny, Judkins Left). The expected non-culprit vessel is filmed first, to assess any collateral filling and/or additional atherosclerotic burden. Thromboaspiration is performed on indication (Thrombolysis In Myocardial Infarction [TIMI] flow 0-1 or evident thrombotic filling defect). Most STEMI patients will receive a limus-eluting stent and be either transferred to peripheral hospital directly after the procedure or remain admitted for 3 days after a successful PCI. Tricks learnt in the elective setting to overcome the sometimes challenging anatomy of the radial artery are very useful before approaching the TRA primary PCI; for instance, balloonguided tracking of the guiding catheter through a radial loop or how to manage subclavian tortuosity. The use of dedicated TRA guiding catheters and/or improvement in handling skills would eventually lead to higher success rates. The TRA expertise accumulated in complex elective procedures will warrant comparable procedural times and success rates in the acute setting. Practice makes, once more, perfect.

Post-procedural Logistics After the TRA, post-procedural bed rest is not necessary, permitting immediate ambulation. This is more comfortable for the patient and reduces the workload of the staff.24 Moreover, prolonged bed rest itself seems to be a predictor of a worse prognosis in coronary artery disease.25 As the TRA enables early discharge, it is associated with a significant reduction in duration of hospital stay and costs.26 These advantages are, of course, more evident in the elective setting, where the TRA allows day care PCI. At OLVG Amsterdam most of the elective TRA PCIs are allowed to go home the same day, provided that the procedural result has been successful and that no complications occur in the first 6 hours after the procedure. In a survey of 397 patients who had undergone an uneventful elective TRA PCI in 2014, 387 of the 397 patients (97.5 %) were allowed to go home the same day, while 10 of the 397 patients (2.5 %) remained in the hospital either because of minor bleedings or suspected angina complaints (unpublished data). Whereas patients who undergo a primary PCI cannot be discharged home on the same day, patients after an uneventful TRA primary PCI can immediately be transferred to a community hospital for surveillance, making the catheter laboratory and coronary care unit available for the following patients. Time for observation can be kept short, as the risk of access site complications is low after the TRA.11 This strategy is of increasing importance, as recent European guidelines dictate that most patients

ICR_Amoroso_FINAL2.indd 90

with ACS should undergo coronary angiography in a PCI-capable centre, within 24 hours of hospital admittance.27 At OLVG Amsterdam, patients are usually transferred to community hospitals 2 hours after a successful TRA primary PCI. Only patients living in the neighbourhood (East and Central Amsterdam: 20–30 %) will remain at OLVG and, also thanks to fast mobilisation, will be discharged home after two or three days. By doing this, the TRA allows us high efficiency and best clinical practices at the same time.

The Issue of Radial Artery Occlusion As a result of its superficial course, the radial artery can be easily punctured and compressed to obtain haemostasis. While serious bleeding complications are uncommon, the TRA bears the risk of radial artery occlusion (RAO). The incidence of RAO varies between 3 % and 10 %, according to different studies and protocols.28,29 RAO rarely results in serious adverse events nor is it symptomatic, but excludes a TRA for future procedures.30 Therefore, any effort should be taken to reduce the risk of RAO. At OLVG Amsterdam, Heparin 5,000 IU is given after sheath insertion during every TRA procedure to retain patency.31 During compression we will also take care that the artery does not get completely occluded and that flow in the radial artery is maintained (‘patent haemostasis‘). With patent haemostasis the incidence of RAO has been shown to decrease by 75.0 % to 1.8 %.32 Finally, the choice of an appropriate sheath size is fundamental. Mismatch between inner diameter of the radial artery and outer diameter of the introducer can cause vascular trauma. A percentage of patients ranging from 14 % to 27 % have a radial artery that is smaller than a 6-French introducer.33 Larger sheath diameter increases the risk of RAO.34 To avoid mismatch between radial artery and introducer, the TRA PCI techniques have been developed with the use of miniaturised catheters and materials, so-called Slender PCI. Both the Slender Club Japan and Europe focus on maximal miniaturisation of the TRA PCI. By using 5-French introducers the chance that the radial artery would be smaller than the introducer is reduced by 50 %.33 In cases where 5-French TRA PCI are performed without the introducer (so-called ’5-French sheathless PCI‘, or ’virtual 3-French PCI‘), the chance to find a radial artery smaller than the introducer is close to 0 %.35 Slender TRA PCIs have shown to be feasible, safe and effective in a variety of elective settings, ranging from bifurcation stenting to straightforward chronic total occlusion.35,36,37 The use of Slender TRA techniques for primary PCI had been at first limited by the availability of compatible materials, in particular thrombus-aspiration catheters, which were until recently only compatible with 6-French or larger guidings. The results of the Randomized Trial of Routine Aspiration Thrombectomy with PCI Versus PCI Alone in Patients with STEMI Undergoing Primary PCI (TOTAL) study changed this scenario, as they showed no significant advantage for systematic on ad-hoc thrombectomy in primary PCI.38 In addition, 5-French compatible thrombus-aspiration catheters are at present available to perform selective aspiration on indication (see Figure 1). At OLVG Amsterdam, where patent haemostasis is applied in all patients and slender TRA techniques are pursued in patients with

INTERVENTIONAL CARDIOLOGY REVIEW

06/10/2016 23:28

Transradial Approach in Primary Percutaneous Coronary Intervention

small radial arteries, we conducted a retrospective survey of patients undergoing a second TRA procedure within 6 months after a first TRA procedure at our centre in 2015 (unpublished data). In 115 of 119 patients (96.6 %), the same radial artery was open and a second TRA was successful. In only two patients (1.6 %) RAO had occurred.

Figure 1: Example of Transradial Approach Primary Percutaneous Coronary Intervention of Acute Inferior Infarction

Indications for Transfemoral Approach in a Transradial High-volume Centre In our experience, the only absolute contraindication for the TRA and reason to switch to the TFA when performing primary PCI is if no radial artery pulsations are felt at both upper extremities. Patients in whom a left internal mammary artery graft needs to be filmed and the left radial artery is not available, or patients with dialysis shunts in the upper extremity, are also relatively contraindicated. Absence of radial artery pulsations can be the result of radial artery occlusion after previous interventions or the result of cardiogenic shock. One could argue that in cases of cardiogenic shock the TFA should be preferred to enable percutaneous mechanical cardiac support. The Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial showed in fact no reduction in mortality when intra-aortic balloon pump (IABP) was used in cardiogenic shock.39 So far, there is no evidence that other types of percutaneous mechanical cardiac support has survival benefits.40 The increased bleeding risk probably outweighs the benefit of improved haemodynamic. Based on these results, routine temporary mechanical support is not pursued at OLVG in acute patients, and IABP and left ventricular (LV) assist devices may be considered for circulatory support only in patients with refractory shock.41 When cardiac support (IABP or Impella device) is needed, our strategy is to first introduce the cardiac support device through one femoral artery and reassess the pulsatility of the radial artery; when feasible, a combined approach can be performed (i.e. TRA primary PCI plus femoral cardiac support device). The TFA is also our bail-out approach

Campeau L. Percutaneous radial artery approach for coronary angiography. Cathet Cardiovasc Diagn 1989;16 :3–7. PMID: 2912567 Kiemeneij F, Laarman GJ. Percutaneous transradial artery approach for coronary stent implantation. Cathet Cardiovasc Diagn 1993;30 :173–8. PMID: 8221875 Windecker S, Kolh Ph, Alfonso F, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35 :2541–619. DOI: 10.1093/eurheartj/ehu278; PMID: 25173339 Howe MJ, Seth M, Riba A, et al. Underutilization of radial access in patients undergoing percutaneous coronary intervention for ST-segment–elevation myocardial infarction: insights from the blue cross blue shield of michigan cardiovascular consortium. Circ Cardiovasc Interv 2015;8. pii:e002036. DOI: 10.1161/CIRCINTERVENTIONS.114.002036; PMID: 25922417 Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33 :2569–619. DOI: 10.1093/eurheartj/ehs215; PMID: 22922416 O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61 :e78–140. DOI: 10.1016/j.jacc.2012.11.019; PMID: 23256914 Kilic S, Van’t Hof AW, Ten Berg J, et al. Frequency and prognostic significance of access site and non-access site bleeding and impact of choice of antithrombin therapy in patients undergoing primary percutaneous coronary intervention. The EUROMAX trial. Int J Cardiol 2016;211 : 119–23. DOI: 10.1016/j.ijcard.2016.02.131; PMID: 26995053 Verheugt FW, Steinhubl SR, Hamon M, et al. Incidence, prognostic impact, and influence of antithrombotic therapy on access and nonaccess site bleeding in percutaneous

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Amoroso_FINAL2.indd 91

10.

11.

12.

13.

14.

15.

A: Tortuous right radial artery with high take-off from the subclavian artery. Guiding Catheter JL4 5-French Sheathless Medikit; B: Distally-occluded Right Coronary Artery (*); C: Result after thromboaspiration; D: Final result after stenting.

in those few cases where the TRA is not successful either because of puncture or navigation failures, or lack of support.

Conclusion Results from our institution and from the literature show that systematically pursuing the TRA for primary PCI results in high procedural success rates and favourable clinical outcomes.18 As also demonstrated by previous studies, this is due to a lower risk of bleeding and lower mortality risk.7,8 The TRA has also the additional advantage of faster patient turn-over and enhanced patient comfort. The TRA is technically challenging and requires a longer learning curve. Moreover, the issue of RAO should not be neglected but rather prevented by patent haemostasis and miniaturisation of catheters (Slender PCI). It is fundamental that both starting and experienced TRA operators will systematically adopt the TRA during elective PCI to optimise their skills, which will eventually lead to comparable door-to-balloon times and procedural outcomes during primary PCI, but with better patient outcomes. Proficiency in the TFA will have to be maintained in cases of bail-out and special circumstances (shock primary PCI). n

coronary intervention. JACC Cardiovasc Interv 2011;4 :191–7. DOI: 10.1016/j.jcin.2010.10.011; PMID: 21349458 Mehran R, Pocock SJ, Stone GW, et al. Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-STelevation acute coronary syndromes: a risk model from the ACUITY trial. Eur Heart J 2009;30 :1457–66. DOI: 10.1093/ eurheartj/ehp110; PMID: 19351691; PMCID: PMC2695951 Kiemeneij F, Laarman GJ, Odekerken D. A randomized comparison of percutaneous transluminal coronary angioplasty by the radial, brachial and femoral approaches: the Access study. J Am Coll Cardiol 1997;29 :1269–75. PMID: 9137223 Jolly SS, Yusuf S, Cairns J, et al. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomized, parallel group, multicentre trial. Lancet 2011;377 :1409–20. DOI: 10.1016/S0140-6736(11)60404-2; PMID: 21470671 Romagnoli E, Biondi-Zoccai G, Sciahbasi A, et al. Radial versus femoral randomized investigation in ST-segment elevation acute coronary syndrome: the RIFLE-STEACS (Radial Versus Femoral Randomized Investigation in ST-Elevation Acute Coronary Syndrome) study. J Am Coll Cardiol 2012;60 :2481–9. DOI: 10.1016/j.jacc.2012.06.017; PMID: 22858390 Weaver AN, Henderson RA, Gilchrist IC, Ettinger SM. Arterial access and door-to-balloon times for primary percutaneous coronary intervention in patients presenting with acute ST-elevation myocardial infarction. Catheter Cardiovasc Interv 2010;75 :695–9. DOI: 10.1002/ccd.22373; PMID: 20146306 Piccolo R, Galasso G, Capuano E, et al. Transradial versus transfemoral approach in patients undergoing percutaneous coronary intervention for acute coronary syndrome. A meta-analysis and trial sequential analysis of randomized controlled trials. PLoS One 2014;9 :e96127. DOI: 10.1371/ journal.pone.0096127; PMID: 24820096; PMCID: PMC4018335 Singh S, Singh M, Grewal N, Khosla S. Transradial vs transfemoral percutaneous coronary intervention in ST-segment elevation myocardial infarction: a systemic review and meta-analysis. Can J Cardiol 2016;32 :777–90. DOI: 10.1016/j.cjca.2015.08.019; PMID: 27233893

16. Valgimigli M, Gagnor A, Calabró P, et al. Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial. Lancet 2015;385 (9986):2465–76. DOI: 10.1016/S01406736(15)60292-6; PMID: 25791214 17. Sibbing D, Kastrati A, Berger PB. Pre-treatment with P2Y12 inhibitors in ACS patients: who, when, why, and which agent? Eur Heart J 2016;37 :1284–95. DOI: 10.1093/eurheartj/ ehv717; PMID: 26712838 18. Adams R, Appelman Y, Bronzwaer JG, et al. Implementation of a prehospital triage system for patients with chest pain and logistics for primary percutaneous coronary intervention in the region of Amsterdam, the Netherlands. Am J Cardiol 2010;106 :931–5. DOI: 10.1016/j.amjcard.2010.05.022; PMID: 20854952 19. Vink MA, Amoroso G, Dirksen MT, et al. Routine use of the transradial approach in primary percutaneous coronary intervention: procedural aspects and outcomes in 2209 patients treated in a single high-volume centre. Heart 2011;97 :1938–42. DOI: 10.1136/heartjnl-2011-300524; PMID: 21880651 20. Ball WT, Sharieff W, Jolly SS, et al. Characterization of operator learning curve for transradial coronary interventions. Circ Cardiovasc Interv 2011;4 :336–41. DOI: 10.1161/CIRCINTERVENTIONS.110.960864; PMID: 21813402 21. Agostoni P, Biodi-Zoccai GGL, De Benedictus L, et al. Radial versus femoral approach for percutaneous coronary diagnostic and interventional procedures - systematic overview and meta-analysis of randomized trials. J Am Coll Cardiol 2004;44 :349–56. DOI: 10.1016/j.jacc.2004.04.034; PMID: 15261930 22. Plourde G, Pancholy SB, Nolan J, et al. Radiation exposure in relation to the arterial access site used for diagnostic coronary angiography and percutaneous coronary intervention: a systematic review and meta-analysis. Lancet 2015;386 :2192–203. DOI: 10.1016/S0140-6736(15)00305-0; PMID: 26411986 23. Montalescot G, van ’t Hof AW, Lapostolle F, et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med 2014;371 :1016–27. DOI: 10.1056/NEJMoa1407024; PMID: 25175921 24. Amoroso G, Sarti M, Bellucci R, et al. Clinical and procedural

06/10/2016 23:28

Coronary

25.

26.

27.

28.

29.

predictors of nurse workload during and after invasive coronary procedures: the potential benefit of a systematic radial access. Eur J Cardiovasc Nurs 2005;4 :234–41. DOI: 10.1016/j.ejcnurse.2005.03.005; PMID: 15914085 Allen C, Glasziou P, Del Mar C. Bed rest: a potentially harmful treatment needing more careful attention. Lancet 1999;354 :1229–33. PMID: 10520630 Amin AP, House JA, Safley DM, et al. Costs of transradial percutaneous coronary intervention. JACC Cardiovasc Interv 2013;6 :827–34. DOI: 10.1016/j.jcin.2013.04.014; PMID: 23871512 Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37 :267–315. DOI: 10.1093/eurheartj/ehv320; PMID: 26320110 Zwaan EM, Koopman AG, Holtzer CAJ, et al. Revealing the impact of local access-site complications and upper extremity dysfunction post transradial percutaneous coronary procedures. Neth Heart J 2015;23 :514–24. DOI: 10.1007/s12471-015-0747-9; PMID: 26437970; PMCID: PMC4608927 Sanmartin M, Gomez M, Rumoroso JR, et al. Interruption of blood flow during compression and radial artery occlusion after transradial catheterization. Catheter Cardiovasc Interv 2007;70 :185–9. DOI: 10.1002/ccd.21058; PMID: 17203470

ICR_Amoroso_FINAL2.indd 92

30. Valgimigli M, Campo G, Penzo C, et al. Transradial coronary catheterization and intervention across the whole spectrum of Allen test results. J Am Call Cardiol 2014;63 :1833–41. DOI: 10.1016/j.jacc.2013.12.043; PMID: 24583305 31. Spaulding C, Lefevre T, Funck F, et al. Left radial approach for coronary angiography: results of a prospective study. Cathet Cardiovasc Diagn 1996;39 :365–70. DOI: 10.1002/(SICI)10970304(199612)39:4<365::AID-CCD8>3.0.CO;2-B; PMID: 8958424 32. Pancholy S, Coppola J, Patel T, Roke-Thomas M. Prevention of radial artery occlusion-patent hemostasis evaluation trial (PROPHET study): a randomized comparison of traditional versus patency documented hemostasis after transradial catheterization. Catheter Cardiovasc Interv 2008;72 :335–40. DOI: 10.1002/ccd.21639; PMID: 18726956 33. Saito S, Ikei H, Hosokawa G, Tanaka S. Influence of the ratio between radial artery inner diameter and sheath outer diameter on radial artery flow after transradial coronary intervention. Catheter Cardiovasc Interv 1999;46 :173–8. DOI: 10.1002/(SICI)1522-726X(199902)46:2<173::AIDCCD12>3.0.CO;2-4; PMID: 10348538 34. Dahm JB, Vogelgesang D, Hummel A, et al. A randomized trial of 5 vs. 6 French transradial percutaneous coronary interventions. Catheter Cardiovasc Interv 2002;57 :172–6. DOI: 10.1002/ccd.10321; PMID: 12357515 35. Kiemeneij F, Yoshimachi F, Matsukage T, et al. Focus on maximal miniaturisation of transradial coronary access materials and techniques by the Slender Club Japan and Europe: an overview and classification. EuroIntervention 2015; 10:1178–86. DOI: 10.4244/EIJY14M09_09; PMID: 25244683 36. Amoroso G, Van Dullemen A, Westgeest P, Van Duinen M.

37.

38.

39.

40.

41.

“Virtual” 3 Fr transradial coronary stenting with the 5 Fr Meito Masamune sheathless guiding catheter: feasibility and safety in an outpatient setting. J Invasive Cardiol 2016;28 :109– 14. PMID: 26689414 Yoshimachi F, Torii S, Naito T. A novel percutaneous coronary intervention technique for chronic total occlusion: Contralateral angiography with a single guiding catheter. Catheter Cardiovasc Interv 2016;87 (6):E229–32. DOI: 10.1002/ ccd.26268; PMID: 26528634 Jolly SS, Cairns JA, Yusuf S, et al. Randomized trial of primary PCI with or without routine manual thrombectomy. N Engl J Med 2015;372 :1389–98. DOI: 10.1056/NEJMoa1415098; PMID: 25853743; PMCID: PMC4995102 Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 2012;367 :1287–96. DOI: 10.1056/NEJMoa1208410; PMID: 22920912 Cheng JM, den Uil CA, Hoeks SE, et al. Percutaneous left ventricular assist devices vs. intra-aortic balloon pump counterpulsation for treatment of cardiogenic shock: a metaanalysis of controlled trials. Eur Heart J 2009;30 :2102–8. DOI: 10.1093/eurheartj/ehp292; PMID: 19617601 Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;18 :891–975. DOI: 10.1002/ejhf.592; PMID: 27207191

INTERVENTIONAL CARDIOLOGY REVIEW

06/10/2016 23:28

Coronary

Expert Opinion Percutaneous Coronary Intervention in Older People: Does Age Make a Difference? Sami A Omar and Adam de Belder Cardiac Services, Brighton and Sussex University Hospitals, Brighton, UK

Abstract As many people are living longer, much older patients are now commonly being seen in clinical practice. The management of coronary disease in this group presents formidable challenges. We review the epidemiology of coronary disease in this population and report on the burden of comorbidity, influence of frailty, problems with polypharmacy, interactions and compliance for the older patient. We discuss the management of stable and acute coronary syndromes, the specific anatomical challenges of the older coronary artery, the outcomes of the limited number of trials involving older patients, and review the guidelines available.

Keywords Older people, comorbidities, percutaneous coronary intervention, quality of life Disclosure: The authors have no conflicts of interest to declare. Received: 4 June 2016 Accepted: 7 September 2016 Citation: Interventional Cardiology Review 2016;11(2):93–7 DOI: 10.15420/icr.2016:20:2 Correspondence: Dr Adam de Belder, Cardiac Services, Brighton and Sussex University Hospitals, Eastern Road, Brighton, BN2 5BE, UK. E: adam.debelder@bsuh.nhs.uk

There will be guidelines about the optimal management of most clinical situations. It makes decision making in medicine more universal, but often you have to think about all of the awkward situations that sit outside the guidelines. One neglected area of research involves the management of illness in older people. The older patient is often not included in trial protocols, and so a well of knowledge is absent for an ever-increasing number of patients. There is an assumption that extending the existing data, acquired from trials conducted on patients sometimes two or three decades younger, to the older individual is adequate. Whatever the clinical scenario, two sides of the argument exist: ‘just because they are old does not mean they should not have what is appropriate’ and ‘these invasive tests are inappropriate and an unkind thing to do to an older person’. This argument underlies the daily predicament of increasingly older patients with multiple comorbidities presenting with coronary syndromes. The challenge for the cardiologist is in making the appropriate decision in every case.

Epidemiology, Comorbidities and Frailty Nutritional and medical advances have increased longevity. Definitions based on chronological age are crude, as biological ageing differs between individuals, but if we use 80 years or above as our marker, the proportion of octogenarians is expected to triple by 2050.1 Not surprisingly, there is an increasing incidence of octogenarian patients presenting with stable angina and acute coronary syndromes.2,3 It is now entrenched in law that age alone cannot influence any aspect of the decision-making process, yet ageing is a fundamental factor to consider when determining the appropriateness of a medical intervention. It requires the physician to use the available tools in an

ICR_de Belder_FINAL2.indd 93

appropriate manner and consider the whole range of comorbidities before choosing a strategy for the presenting problem. Older people are a different cohort of patients, as the deterioration of various organs has a detrimental effect on vision, hearing, mobility, renal function, cerebral function and cognition.4–6 All of these factors individually or in combination can contribute to a final management plan. It is true of many interventions, but particularly cardiac interventions (structural and coronary), that successfully resolved cardiac symptoms may have little impact on the overall burden of other morbidities, and so the overall improvement in the patient’s quality of life is marginal. Thus, when considering invasive or surgical intervention in the older age group, it is important to emphasise that any favourable impact on the patient’s clinical outcome and quality of life will be limited to the resolution of his or her cardiac symptoms.7–9 Frailty reflects a reduction in physiological reserve and is widely recognised as a predictor for poor health outcomes in the older population.10 It is difficult to define frailty in a satisfactory and comprehensive manner. Is it a physical component dependent on nutrition and muscle bulk that influences strength and endurance? Or is it mental, affecting mood and cognition? More than 20 scoring systems and diagnostic tools have been devised to quantify frailty and its impact on outcomes with regards to cardiovascular disease.11 Some of these tools, such as the Charlson index12 or the outcome-based frailty index13 can be extremely helpful when attempting to decide on how aggressively to manage an older person. Upward of 40 studies were published in the 4 years between 2010 and 2014 attempting to address frailty in the context of cardiovascular disease;11,14,15 however, none were able to encompass the vast scope and spectrum this term covers.10

Access at: www.ICRjournal.com

06/10/2016 23:54

Coronary Although the majority of the above studies assessed mortality following a cardiac event or procedure, 11,14,15 it is important to note that many of the older population will value quality of life over mortality risk or benefit, in essence wanting quality rather than quantity. Using percutaneous coronary intervention (PCI) to treat symptoms reduces hospital readmissions but leads to increased frailty physically, through loss of muscle bulk, and mentally, through loss of confidence.16 The trajectory of the frailty may also vary, not only through the event but with the treatment option adopted: PCI versus coronary artery bypass grafting (CABG) versus medical therapy.17

Analysis of the UK PCI (British Cardiovascular Intervention Society/ National Institute for Cardiovascular Outcomes Research) database shows that major adverse cardiac event rates for older patients with stable angina are low and compare favourably to a younger cohort. Often the function of intervention is resolution of difficult symptoms, however, and pursuing strategies for longer-term mortality benefit when one is >80 years of age is difficult to justify, particularly when the intervention involves major heart surgery. There is a small amount of literature on highly selective patients demonstrating good mortality results from cardiac surgery,23 but it is often the morbidity of surgery that leaves the older patient reeling.

There is an age-related decline in cognition, and an increasing likelihood of dementia over time.4–6 The presence of cognitive decline makes treatment decisions difficult, as these matters are rarely binary and the rate of decline can be very variable. The authors believe, however, that it is generally accepted that cardiac interventions in patients with dementia are rarely appropriate. This can raise challenges in the acute setting, when patients require emergency angioplasty for ST elevation myocardial infarction (STEMI), or emergency pacing, when the lack of opportunity to discuss the broader context might lead to inappropriate intervention.

Non-ST Segment Myocardial Infarction

Percutaneous Coronary Intervention in Older People Revascularisation strategies for patients with stable angina and the acute coronary syndromes (ACS) are based on multiple trials and are coalesced within guideline recommendations from various associations.18–20 These trials are based on patients with a mean age of about 60 years. There are many subgroups of patients that benefit from surgical revascularisation, with evidence for improved survival, but when it comes to the prospect of an octogenarian undergoing surgery it is the morbidity and recovery that are the main stumbling blocks. For example, permanent diasability due to stroke is much more likely in octogenarian patients undergoing CABG when compared with PCI (2.84 % versus 0.57 %),21 and so many of these patients undergo PCI as a suitable alternative.

Coronary Syndromes Stable Angina The older patient is more likely to have multivessel disease, calcified and tortuous anatomy, chronic total occlusions, poor left ventricular function, renal impairment and concomitant valvular disease. Fortunately, there is little coronary disease that cannot be treated by percutaneous means. Remarkable technological advances allow the modern interventional operator to deal with obstructive calcium, rigid tortuosity, challenging left main coronary anatomy and chronic total occlusions with little collateral complication.8 Although the Trial of Invasive versus Medical Therapy in Elderly patients with chronic symptomatic coronary-artery disease (TIME) is dated, it stands out as the only randomised-controlled trial comparing medical therapy to invasive management in older patients with stable angina. A relatively small number of patients (305 patients, >75 years) with symptomatic chronic stable angina were randomised to invasive investigation and treatment (PCI or CABG) or optimal medical therapy. At 6 months the investigation and treatment group had better symptom relief and quality of life, in addition to having fewer major events, when compared to the medical arm (49 % versus 19 %).22

ICR_de Belder_FINAL2.indd 94

The main trials that steered the management of patients to an invasive strategy with a view to revascularisation had cohorts with a mean age of 61 years,24–26 and the concept that all patients should have angiography and revascularisation if appropriate is enshrined in cardiac practice. A meta-analysis has shown that the benefits were greater in the older patients within the various trials,27 but it is unclear where the benefit gained starts to flatten out. The line cannot continue to be straight and upward. Indeed, as many physicians think it inappropriate to subject older patients to invasive investigations and treatment as think it criminal not to. Each patient deserves to be judged on his or her individual performance status, as biological age often does not represent chronological age. There is considerable individual variation in relation to the presence of comorbidities and physical capabilities. Octogenarians are woefully under-represented in the trial data, and where there are data, very few come from randomised-controlled trials.28 Most data come from large registry data sets.29,30 In initial trials published including data from the Non-ST-Segment Elevation – ACS (NSTE-ACS) European registry, roughly a third (27–34 %) of patients are aged ≥75 years, but this proportion has dropped to no more than 20 % of all patients in recent trials. Even when older patients are recruited into clinical trials, they are highly selected, often having substantially less comorbidity than patients encountered in daily clinical practice.31–33 The rate of mortality for those aged >75 years is twice that of those aged <75 years and the prevalence of ACS-related complications, such as heart failure, bleeding, stroke, renal failure and infections, markedly increases with age.34 In addition to this, the older patient is less likely to be treated invasively.35 A subgroup analysis of the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy – Thrombolysis In Myocardial Infarction (TACTICS-TIMI 18) trial, however, found that patients >75 years of age with NSTE-ACS derived the largest benefit, in terms of both relative and absolute risk reductions, from an invasive strategy at the cost of an increase in risk of major bleeding and need for transfusions.28 There are on-going randomised prospective multicentre trials attempting to address the lack of research data. The Revascularisation or Medical Therapy in Elderly Patients with acute angina syndromes (the RINCAL study, NCT02086019) is actively recruiting and randomising patients with non-ST segment elevation myocardial infarction to initial conservative management with a view to invasive assessment and treatment if conservative measures fail versus invasive assessment for all, thus including angiography as part of the management whatever the clinical circumstance. The primary endpoint is death from cardiovascular cause and myocardial infarction at 1 year. The results of this study will be available in 2018.

INTERVENTIONAL CARDIOLOGY REVIEW

06/10/2016 23:54

PCI in Older People

STEMI Immediate PCI for patients with STEMI is now the treatment of choice, if appropriate expertise is available to perform it in a timely manner. Older patients have more to gain from primary angioplasty, but they can provide a challenge to the interventionalist as they are more likely to be sicker, have less ventricular function to work with, have an increased likelihood of significant comorbidity and have more challenging coronary anatomy. There has to be some judgement about appropriateness in each case, but often the lines are blurred about clinical appropriateness, particularly when decisions to treat have to be made quickly in order to secure the benefit. The European Society of Cardiology (ESC) guidelines on the management of acute myocardial infarction in patients presenting with persistent ST-segment elevation offer no specific guidance for octogenarians.36 The guidelines do, however, acknowledge that these patients are at a higher risk of side effects from medical treatment, including the risk of bleeding following treatment with antiplatelet agents and anticoagulants, hypotension, bradycardia and renal failure. In addition to the intrinsic bleeding risk of older people, as a group they are more frequently exposed to excessive doses of antithrombotic drugs that are excreted by the kidney, which can cause a problem due to age-related decline in kidney function.36 Data from the Myocardial Infarct National Audit Project (MINAP) in the UK show substantially differing management practices in different centres. The IMAP analysis suggests that reduced mortality in older people was directly correlated to whether or not a primary angioplasty procedure was performed.37 It is clear that it is entirely inappropriate to deny patients treatment for their heart condition based on their age alone. Brighton and Sussex University Hospitals’ practice activates the primary angioplasty team for all STEMI patients. The only time the team does not plan to intervene urgently is when the patient has arrived in the catheter laboratory and been clinically assessed.

Figure 1: Example of Rotational Atherectomy, Ballooning and Drug-eluting Stent Placement in an Older Patient A

A 92-year-old woman presented with intractable angina with (A) calcified ostial right coronary artery stenosis and (C) complex left main stem calcific disease and diffuse left anterior descending atheroma. Both instances of coronary disease – (B) right and (D) left – were treated by rotational atherectomy and drug-eluting stent placement.

surgery to place drug-eluting stents should lead to increased rates of stent thrombosis, although the limited data available in this age group have not shown this to be a clinical concern.31,32 Similarly, the data on the use of high-dose statins could be challenged in this age group, as older people were excluded from the statin trials on which decisions to treat are based, and there may be a counterargument that individuals in this age group run a higher risk of developing statininduced myositis.

Specific Coronary Anatomical Subsets Calcification

Multiple Drugs and Drug Interactions As diagnoses accumulate with time, the drug list grows. With the zealous processes in place to ensure that conditions are treated with the correct plethora of drugs, the pressure to prescribe is significant. This is particularly notable for cardiovascular conditions, where optimal management for heart failure, atherosclerosis and cardiac revascularisation all involve the prescription of multiple agents.36,38 The management of cardiac disease within the older age group is riddled with the conflict between lean prescribing, with fewer interactions and side effects, and the evidence-based prescribing of high doses of multiple agents.39 Many of the trials influencing decision-making in cardiovascular medicine are based on populations with a mean age in their early 60s, however, as older age is usually an exclusion criterion because of the increased possibility of events that may be unrelated to the trial question. Thankfully, there are trials emerging that are investigating the role of medical intervention in the older age group. The results of these trials will be invaluable in guiding future decision making.

Compliance Not surprisingly, it is more likely for the senior citizen to be noncompliant with their multiple drugs.40 One would have thought this would have implications for patients with drug-eluting stents, for example. A failure to take dual antiplatelet regimens religiously after

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_de Belder_FINAL2.indd 95

Vascular calcification is a complex and poorly-understood biological phenomenon. The idea that bony cells deposit within the vascular tree is a strange one. The condition is more likely to occur in patients with hypertension, diabetes or renal impairment and the incidence increases with age.41 There are some data supporting the belief that coronary calcification is an independent predictor of mortality.42 Any interventional operator with a sizeable octogenarian patient group will need to be adept at managing the heavily-calcified artery. The reduction in wall compliance can lead to inadequate lumen expansion with incomplete stent apposition, leading to increased rates of stent thrombosis and the requirement for target-lesion revascularisation. Lesion preparation with rotational atherectomy has reduced these unwelcome complications, but complications remain more likely.43,44 In the authors’ analysis of more than 2,000 patients undergoing rotational atherectomy prior to stenting within the UK, it was found that there was less procedural success when compared with a cohort of patients not requiring rotational atherectomy (90.3 versus 94.6 %; p<0.001) and complications were more frequent (9.7 versus 5.4 %; p<0.001). After 2.4 ± 1.2 years’ follow-up, there was slightly poorer survival for patients undergoing rotational atherectomy, even after adjustment for adverse variables and following propensity analysis.45 An example of critical coronary disease due to severe calcification and its successful management is shown in Figure 1.

06/10/2016 23:54

Coronary Tortuosity Tortuous vessels can provide unwelcome resistance to optimal stenting. The passage of a rigid tube around tight corners has proved problematic in some cases. Improvements in stent design and morphology, stiffer wires and mother-and-child catheters have allowed the resolution of most of these hurdles, but occasionally calcified tortuous angles remain defiant to stent placement.

When to Use Bare Metal and Drug-eluting Stents There are a number of theoretical concerns about using drug-eluting stent technology in the octogenarian cohort. Potential problems with compliance with dual antiplatelet therapy might increase stent thrombosis rate, and the increased possibility of significant bleeding complications with the longer duration of dual antiplatelet therapy would suggest that bare metal stenting might have a role. This hypothesis was tested in the multicentre prospective Xience or Vision Stents for the Management of Angina in the Elderly (XIMA) trial comparing patients randomised to drug-eluting stents (n=399) or bare-metal stents (n=401). The XIMA trial found similar rates of all-cause death, stroke and major haemorrhage, but a reduced incidence of myocardial infarction and target vessel revascularisation in the drug-eluting stent group.31 More recently, the LEADERS FREE Investigators compared a polymerfree Biolimus-A9 drug-coated stent with a bare-metal stent in 2,466 patients considered at high risk of bleeding, many of whom were older.32 What is unique about the trial is that both arms took only 1 month of dual antiplatelet therapy. There was a reduction in the primary safety endpoint for the coated stent (9.4 versus 12.9 %) with a significant reduction in target lesion revascularisation as well.32 Finally, the SYNERGY II Everolimus eluting stent In patients >75 years undergoing coronary Revascularisation associated with a short dual antiplatelet therapy (SENIOR) trial is comparing a third-generation drug-eluting stent with a bare-metal stent in 1,200 patients aged ≥75 years undergoing coronary stenting.33 Both arms will receive the same length of dual antiplatelet therapy – 1 month for stable angina and 6 months for acute coronary syndromes. The final results will be available in 2017.33

Centers for Disease Control and Prevention, Trends in aging-United States and worldwide. MMWR Morb Mortal Wkly Rep 2003;52 :101–4, 106. PMID: 12645839 Rich MW. Epidemiology, clinical features, and prognosis of acute myocardial infarction in the elderly. Am J Geriatr Cardiol 2006;15 :7–11. PMID: 16415640 Kozlov KL, Bogachev AA. Coronary revascularization in the elderly with stable angina. J Geriatr Cardiol 2015;12 :555–68. DOI: 10.11909/j.issn.1671-5411.2015.05.017; PMID: 26512248 Linden T, Samuelsson H, Skoog I, et al. Visual neglect and cognitive impairment in elderly patients late after stroke. Acta Neurol Scand 2005;111 :163–8. PMID: 15691284 Deal JA, Betz J, Yaffe K, et al. Hearing impairment and incident dementia and cognitive decline in older adults: the Health ABC Study. J Gerontol A Biol Sci Med Sci 2016: glw069. DOI: 10.1093/gerona/glw069; PMID: 27071780: epub ahead of press Lo Coco D, Lopez G, Corrao S. Cognitive impairment and stroke in elderly patients. Vasc Health Risk Manag 2016;12 : 105–16. DOI: 10.2147/VHRM.S75306; PMID: 27069366 Kaehler J, Meinertz K, Hamm CW. Coronary interventions in the elderly. Heart 2006;92 :1167–71. DOI: 10.1136/ hrt.2005.071266; PMCID: PMC1861131 Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS); European Association for Percutaneous Cardiovascular Interventions (EAPCI), Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J 2010;31 :2501–55. DOI: 10.1093/ eurheartj/ehq277; PMID: 20802248 de Boer SP, Westerhout CM, Simes RJ, et al.; Primary Coronary Angioplasty Versus Thrombolysis-2 (PCAT-2) Trialists Collaborators Group. Mortality and morbidity

ICR_de Belder_FINAL2.indd 96

10.

11.

12.

13.

14.

15.

16.

These trials have covered new territory, with the inclusion of an increasing number of older patients helping to define evidencebased decisions. It looks increasingly likely, based on emerging evidence, that the bare-metal stent will be confined to history.

ESC Guidelines The ESC guidelines for myocardial revascularisation were updated in 2014, and offer guidance on revascularisation strategies for patients with both stable and unstable ACS symptoms. 46 Myocardial revascularisation has been subject to more randomised clinical trials than almost any other intervention, however all four ESC guidelines acknowledge a number of significant limitations with regard to their use in octogenarians. To summarise, the ESC acknowledges that: • As a population, octogenarians are usually undertreated and under-represented in clinical trials, irrespective of presentation, meaning that if we follow the trial results we are often extrapolating data into routine clinical practice. • Octogenarians have a higher prevalence of comorbidities. • They are difficult to diagnose due to atypical symptoms. • Patients are more often referred for PCI than CABG, but age should not be the sole criterion determining the choice of type of revascularisation. • They are at higher risk of complications during and after coronary revascularisation, irrespective of modality.

Conclusion Age does make a difference to PCI outcomes in older people, but it is never the sole arbiter of any clinical decision, whether in relation to the heart or any other aspect of health. The management of any coronary syndrome will depend on issues of frailty, appropriateness, cognition, drug interactions, compliance and the feasibility of safe revascularisation. There are specific hazards associated with PCI in older arteries, but competence with modern coronary revascularisation techniques will allow safe outcomes for the majority of patients. In practice, the key decisions are usually made before the patient enters the catheter laboratory. n

reduction by primary percutaneous coronary intervention is independent of the patient’s age. JACC Cardiovasc Interv 2010;3 :324–31. DOI: 10.1016/j.jcin.2009.11.022; PMID: 20298993 Berrut G, Andrieu S, Araujo de Carvalho I, et al. Promoting access to innovation for frail old persons. IAGG (International Association of Gerontology and Geriatrics), WHO (World Health Organization) and SFGG (Société Française de Gériatrie et de Gérontologie) Workshop--Athens January 20-21, 2012. J Nutr Health Aging 2013;17 :688–93. DOI: 10.1007/ s12603-013-0039-2; PMID: 24097023 Afilalo J, Alexander KP, Mack MJ, et al. Frailty assessment in the cardiovascular care of older adults. J Am Coll Cardiol 2014;63 :747–62. DOI: 10.1016/j.jacc.2013.09.070; PMID: 24291279 Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40 :373–83. PMID: 3558716 Bouillon K, Kivimaki M, Hamer M, et al. Measures of frailty in population-based studies: an overview. BMC Geriatr 2013;13 :64. DOI: 10.1186/1471-2318-13-64; PMID: 23786540 Furukawa H, Tanemoto K. Frailty in cardiothoracic surgery: systematic review of the literature. Gen Thorac Cardiovasc Surg 2015;63 :425–33. DOI: 10.1007/s11748-015-0553-8; PMID: 25916404 Jha SR, Ha HS, Hickman LD, et al. Frailty in advanced heart failure: a systematic review. Heart Fail Rev 2015;20 :553–60. DOI: 10.1007/s10741-015-9493-8; PMID: 25982016 Bouillon K, Batty GD, Hamer M, et al. Cardiovascular disease risk scores in identifying future frailty: the Whitehall II prospective cohort study. Heart 2013;99 :737–42.

DOI: 10.1136/heartjnl-2012-302922; PMID: 23503403 17. Freiheit EA, Hogan DB, Patten SB, et al. Frailty trajectories after treatment for coronary artery disease in older patients. Circ Cardiovasc Qual Outcomes 2016;9 :230–8. DOI: 10.1161/ CIRCOUTCOMES.115.002204; PMID: 27166209 18. Hannan EL, Cozzens K, Samadasvili Z, et al. Appropriateness of coronary revascularization for patients without acute coronary syndromes. J Am Coll Cardiol 2012;59 :1870–6. DOI: 10.1016/j.jacc.2012.01.050; PMID: 22595405 19. Graham MM, Norris CM, Galbraith PD, et al.; APPROACH Investigators. Quality of life after coronary revascularization in the elderly. Eur Heart J 2006;27 :1690–8. PMID: 16717072 20. Cohen DJ, van Hout B, Serruys PW, et al., for the Synergy between PCI with Taxus and Cardiac Surgery (SYNTA) Investigators. Quality of life after PCI with drug-eluting stents or coronary-artery bypass surgery. N Engl J Med 2011;364 :1016–26. DOI: 10.1056/NEJMoa1001508; PMID: 21410370 21. Dacey LJ, Likosky DS, Ryal TJ Jr, et al.; Northern New England Cardiovascular Disease Study Group. Long-term survival after surgery versus percutaneous intervention in octogenarians with multivessel coronary disease. Ann Thorac Surg 2007;84 :1904–11; discussion 1904–11. PMID: 18036905 22. TIME Investigators. Trial of invasive versus medical therapy in elderly patients with chronic symptomatic coronary-artery disease (TIME): a randomised trial. Lancet 2001;358 :951–7. PMID: 11583747 23. Ozen A, Unal EU, Songur M et al. Coronary artery bypass surgery in the octogenarian – should we intervene or leave them be? J Geriatr Cardiol 2015;12:147–52. DOI: 10.11909/j. issn.1671-5411.2015.02.005; PMID: 25870618 24. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised

INTERVENTIONAL CARDIOLOGY REVIEW

06/10/2016 23:54

PCI in Older People

25.

26.

27.

28.

29.

30.

31.

32.

multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease Investigators. Lancet 1999;354:708–15. PMID: 10475181 Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Eng J Med 2001;344:1879–87. DOI: 10.1056/NEJM200106213442501; PMID: 11419424 Fox KA, Poole-Wilson PA, Henderson RA, et al.; Randomized Interventionl Trial of unstable Angina Investigators. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomized Intervention Trial of unstable Angina. Lancet 2002;360:743–51. PMID: 12241831 Manfrini O, Ricci B, Dormi A, et al. Early invasive strategy for unstable angina: a new meta-analysis of old clinical trials. Sci Rep 2016;6:27345. DOI: 10.1038/srep27345 Bach RG, Cannon CP, Weintraub WS, et al. The effect of routine, early invasive management on outcome for elderly patients with non-ST-segment elevation acute coronary syndromes. Ann Intern Med 2004;141 186–95. PMID: 15289215 Barywani SB, Li S, Lindh M, et al. Acute coronary syndrome in octogenarians: association between percutaneous coronary intervention and long-term mortality. Clin Interv Aging 2015;10 :1547–53. DOI: 10.2147/CIA.S89127; PMID: 26451095 Fach A, Bünger S, Zabrocki R, et al. Comparison of outcomes of patients with ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention analyzed by age groups (<75, 75 to 85, and >85 years); (results from the Bremen STEMI Registry). Am J Cardiol 2015;116 :1802–9. DOI: 10.1016/j.amjcard.2015.09.022; PMID: 26602071 de Belder A, de la Torre Hernandez JM, Lopez-Palop R, et al.; XIMA Investigators. A prospective randomized trial of everolimus-eluting stents versus bare-metal stents in octogenarians: the XIMA Trial (Xience or Vision Stents for the Management of Angina in the Elderly). J Am Coll Cardiol 2014;63 :1371–5. DOI: 10.1016/j.jacc.2013.10.053; PMID: 24216285 Urban P, Meredith IT, Abizaid A, et al., for the LEADERS FREE

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_de Belder_FINAL2.indd 97

33.

34.

35.

36.

37.

38.

39.

Investigators. Polymer-free drug-coated coronary stents in patients at high bleeding risk. N Engl J Med 2015;373 :2038–47. DOI: 10.1056/NEJMoa1503943 Varenne O, Cuisset T, Chaïb A, et al. The SYNERGY II Everolimus elutiNg stent In patients Older than 75 years undergoing coronary Revascularisation associated with a short dual antiplatelet therapy (SENIOR) trial: rationale and design of a large-scale randomised multicentre study. EuroIntervention 2015;11 :20150220-08. DOI: 10.4244/ EIJY15M12_02; PMID: 26690312 Fox KA, Clayton TC, Damman P, et al; FIR Collaboration. Long-term outcome of a routine versus selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome a meta-analysis of individual patient data. J Am Coll Cardiol 2010;55:2435–45. DOI: 10.1016/j. jacc.2010.03.007; PMID: 20359842 Rosengren A, Wallentin L, Simoons M, et al. Age, clinical presentation, and outcome of acute coronary syndromes in the Euroheart acute coronary syndrome survey. Eur Heart J 2006;27 :789–95. PMID: 16464911 Task Force Members, Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34:2949–3003. DOI: 10.1093/eurheartj/eht296; PMID: 23996286 Herrett E, Smeeth L, Walker L, Weston C; MINAP Academic Group. The Myocardial Ischaemia National Audit Project (MINAP). Heart 2010;96:1264–7. DOI: 10.1136/ hrt.2009.192328; PMID: 20659944 McMurray JJ, Adamopoulos S, Anker SD, et al.; ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33 :1787–847. DOI: 10.1093/eurheartj/ehs104; PMID: 22611136 Chrischilles EA, Schneider KM, Schroeder MC, et al. Association between preadmission functional status and use and effectiveness of secondary prevention medications in

40.

41.

42.

43.

44.

45.

46.

elderly survivors of acute myocardial infarction. J Am Geriatr Soc 2016;64 :526–35. DOI: 10.1111/jgs.13953; PMID: 26928940 Mortazavi SS, Shati M, Keshtkar A, et al. Defining polypharmacy in the elderly: a systematic review protocol. BMJ Open 2016;6 :e010989. DOI:10.1136/bmjopen-2015010989 Sage AP, Tintut Y, Demer LL. Regulatory mechanisms in vascular calcification. Nat Rev Cardiol 2010;7:528–36. DOI: 10.1038/nrcardio.2010.115; PMID: 20664518 Schenker MP, Dorbala S, Hong EC, et al. Interrelation of coronary calcification, myocardial ischemia, and outcomes in patients with intermediate likelihood of coronary artery disease: a combined positron emission tomography/ computed tomography study. Circulation 2008;117 :1693–700. DOI: 10.1161/CIRCULATIONAHA.107.717512; PMID: 18362235 Abdel-Wahab M, Richardt G, Joachim Büttner H, et al. Highspeed rotational atherectomy before paclitaxel-eluting stent implantation in complex calcified coronary lesions: the randomized ROTAXUS (Rotational Atherectomy Prior to Taxus Stent Treatment for Complex Native Coronary Artery Disease) trial. JACC Cardiovasc Interv 2013;6 :10–9. DOI: 10.1016/ j.jcin.2012.07.017; PMID: 23266232 Parikh K, Chandra P, Choski N, et al. Safety and feasibility of orbital atherectomy for the treatment of calcified coronary lesions: the ORBIT I trial. Catheter Cardiovasc Interv 2013;81 :1134–9. DOI: 10.1002/ccd.24700; PMID: 23460596 Cockburn J, Hildick-Smith D, Cotton J, et al. Contemporary clinical outcomes of patients treated with or without rotational coronary atherectomy--an analysis of the UK central cardiac audit database. Int J Cardiol 2014;170 :381–7. DOI: 10.1016/j.ijcard.2013.11.018; PMID: 24289876 Authors/Task Force Members, Windecker S, Kolh P, Alfonzo F, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35 :2541–619. DOI: 10.1093/eurheartj/ehu278; PMID: 25173339

06/10/2016 23:54

Coronary

Preventing Contrast-induced Renal Failure: A Guide Mic h e l a Fa g g i o n i 1 ,2 a n d Ro x a n a M e h ra n 1 1. Interventional Cardiovascular Research and Clinical Trials, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; 2. Cardiac Thoracic and Vascular Department, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy

Abstract Contrast-induced acute kidney injury (CI-AKI) is characterised by a rapid deterioration of renal function within a few days of parenteral administration of contrast media (CM) in the absence of alternative causes. CI-AKI is the most common form of iatrogenic kidney dysfunction with an estimated prevalence of 12 % in patients undergoing percutaneous coronary intervention. Although usually selfresolving, in patients with pre-existing chronic kidney disease (CKD) or concomitant risk factors for renal damage, CI-AKI is associated with increased short- and long-term morbidity and mortality. Therefore, risk stratification based on clinical and peri-procedural characteristics is crucial in selecting patients at risk of CI-AKI who would benefit the most from implementation of preventive measures.

Keywords Contrast-induced nephropathy, prevention, risk score, chronic kidney disease Conflicts of Interest: MF has no disclosures. RM has received research grant support form Eli Lilly/DSI, BMS; AstraZeneca, The Medicines Company, OrbusNeich, Bayer and CSL Behring. She has worked as a consultant for Janssen Pharmaceuticals, Inc., Osprey Medical Inc., Watermark Research Partners and Medscape. She is on the advisory board of Abbott Laboratories. She has equity in Claret Medical Inc., Elixir Medical Corporation. She has given industry sponsored lectures (without any marketing purpose) for PlatformQ, Sanofi-aventis, other activities comprise but are not limited to, committee participation, data safety monitoring board (DSMB) membership for Covidien and Forest Laboratories (no payment). Received: 9 March 2016 Accepted: 11 May 2016 Citation: Interventional Cardiology Review, 2016;11(2):98–104 DOI: 10.15420/icr.2016:10:2 Correspondence: Roxana Mehran, MD, FAHA, Mount Sinai Hospital, One Gustave L. Levy Place, Box 1030, New York, NY 10029, USA. E: roxana.mehran@mountsinai.org

With the increasing use of contrast agents for both diagnostic and interventional procedures, contrast-induced acute kidney injury (CI-AKI) has become an important medical concern. It is estimated that CI-AKI is the third most common cause of hospital-acquired renal failure and has significant prognostic implications for patients outcomes.1 The incidence of CI-AKI varies depending on the definitions and cut-off values used. Although serum creatinine is subject to fluctuation during the hospital stay and is influenced by multiple factors, it is an easy, cost-effective way to estimate kidney function and therefore it is usually used to determine CI-AKI.2 The most common definition of CI-AKI comprises an absolute increase in serum creatinine levels of ≥0.5 mg/dl (44 µmol/l) or a ≥25 % relative rise from baseline within 72 hours from contrast media (CM) exposure. Importantly, alternative etiologies for kidney injury, such as microembolism or severe hypotension should be excluded. Overall, the incidence of CI-AKI in the general population is reported to be 0.6–2 %.3 However, the prevalence is higher in patients undergoing coronary angiography and percutaneous coronary interventions, most likely due to high CM volumes used during these procedures and the type of patients treated, often presenting multiple comorbidities.1,3 A sub-analysis of the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) and Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) randomised clinical trials has reported a frequency of CI-AKI of 12.5 % after percutaneous coronary interventions (PCI).4 In older patients with preexisting renal dysfunction, particularly if associated with diabetes or congestive heart failure (CHF), the frequency of CI-AKI further rises to be >20–30 %.3,5,6

Access at: www.ICRjournal.com

ICR_Mehran_FINAL2.indd 98

Natural History of CI-AKI While in most cases CI-AKI is self-limiting and creatinine or estimated glomerular filtration rate (eGFR) return to baseline levels in 5–10 days, in patients with a high risk profile for kidney damage, CI-AKI is associated with increased rates of in-hospital and short-term outcomes. Rihal et al. observed a dramatically higher rate of in-hospital mortality in patients undergoing PCI who developed CI-AKI (22 versus 1.4 %; p<0.0001).7 Similarly, Form et al. reported that CI-AKI, following contrastenhanced procedures, was associated with an increased risk for 30-day mortality after adjustment for potential confounding variables (odds ratio [OR] 3.37; 95 % confidence interval [CI]; [2.58–4.41]).8 Even small increases of serum creatinine, greater than 0.25 mg/dl but lower than the commonly used threshold of 0.5 mg/dl, after coronary angiography seem independently associated with prolonged in-hospital stay and with increased in-hospital mortality.9 In addition to short-term complications, CI-AKI can have repercussions on longterm renal function and can precipitate chronic kidney disease (CKD) progression.10 An observational study has recently estimated that patients with CI-AKI have a 4–17-fold higher risk of renal impairment at 3 months after index PCI depending on the severity of post procedural CI-AKI.11 Moreover, CI-AKI has been associated with significantly higher mortality rates at 1 year (9.8 versus 2.9 %; p<0.0001) compared to patients undergoing uncomplicated PCI. Similarly, the 1-year rate of myocardial infarction (MI), definite/probable stent thrombosis, target lesion revascularisation and major bleeding (13.8 versus 5.4 %; hazard ratio [HR] 2.64 [2.21–3.15]; p<0.0001) were also higher in patients with CI-AKI, even after multivariable adjustment.4 Consistent with these results, Solomon et al. demonstrated a greater

07/10/2016 00:12

Contrast‐induced Renal Failure

than threefold rise in adverse events (death, stroke, MI, end-stage renal disease requiring renal replacement therapy) at 1 year after angiography in patients with CI-AKI defined with a lower cut-off threshold of 0.3 mg/dl of absolute creatinine increase.12 Finally, CI-AKI has also been linked to higher 5-year mortality rates after PCI. Despite the difficulty to account for the progression of comorbidities and other risk factors that could explain the different mortality rates between patients with and without CI-AKI, results have been consistent across various prospective studies.7,13,14 Therefore, implementation of preventive measures is crucial to reduce frequency of CI-AKI and avoid short- and long-term clinical outcomes.

Table 1: Risk Factors for Contrast-induced Acute Kidney Injury

Pathophysiology of Contrast-induced Nephropathy

nephrons of CKD animal models with a consequent deficiency of medullary oxygen that would predispose to the ischaemic damage observed in CI-AKI.27 In patients with CKD, Moore et al. and Barrett et al. described an increase from 4 to 20 % in the incidence of CI-AKI as the baseline serum creatinine level rose from 1.2 to 2.9 mg/dl.28 In addition, a larger decrement in eGFR 2 years following the procedure has been observed in patients with CKD who experienced transient CI-AKI after coronary angiography (eGFR at 2 years, -20 ± 11 ml/min 1.73 m2 versus -6 ± 16 ml/min/1.73 m2; p=0.02).13 Since accurate determination of kidney function is so critical in CKD patients undergoing CM exposure, direct measurement of the creatinine clearance (CrC) or estimation of GFR with the MDRD equation is preferable to serum creatinine in order to assess renal function. CrC or eGFR should be estimated in high-risk patients before the procedure and at various points during the post-procedural follow-up.

CM is almost completely eliminated by the kidney approximately 30–60 minutes after administration. The mechanisms of CM nephrotoxicity are complex and not fully understood. However, for the purpose of this review the process can be simplified into three main components: parenchymal ischaemia, direct and indirect tubular cell injury and direct and indirect damage of the vascular endothelium. In brief, upon administration of CM, a transient vasodilation with increase in renal blood supply has been observed, quickly followed by a reduction of blood flow and GFR.15 The mechanisms involved include decreased production of vasodilating agents such as prostaglandin and nitric oxide (NO), impaired endothelial function and vasoconstriction of the vasa recta.16 The ensuing parenchymal ischaemia becomes more relevant in the outer medulla where oxygen delivery is scarce even in physiological conditions because of the anatomical distribution of the vasa recta.16,17 As a result of renal hypoxia, reactive oxygen species (ROS) are produced that then can damage both the tubular cells and the vascular endothelium.18,19 In addition, the CM filtered by the glomeruli is concentrated in the tubular lumen through extra-tubular fluid reabsorption.20 Direct contact of CM can injure tubular cells and induce apoptosis through the activation of shock proteins.21–23 These effects vary depending on the osmolarity and ionic strength of the CM.19 Furthermore, CM increases urinary viscosity in the tubules and can determine slow flow, thus prolonging the exposure of tubular cells to the CM, and high intratubular pressure that further exacerbates medullary ischaemia by compressing the vasa recta.20,24 Additionally, the slow blood flow in the restricted vasa recta will increase the contact time of CM with the vascular endothelium contributing to its damage.

Risk Factors Risk scores have been developed to predict CI-AKI and identify patients who would benefit from preventive measures. The Mehran model includes both clinical and peri-procedural risk factors: congestive heart failure (CHF) (5 points), hypotension (5 points), eGFR (4 points), age >75 years (4 points), diabetes (3 points), anaemia (3 points) and contrast volume (1 point for every 100 cc used). Based on the overall score patients can be stratified into four different risk categories: low (score ≤5) moderate (score 6–10), high (score 11–15) or very high risk (score ≥16).25 Similarly, Brown et al. have validated a model consisting of pre-procedural variables only, such as serum creatinine, CHF, diabetes, urgent or emergency priority, intra-aortic balloon pump use, age ≥80 years and female sex.26 Both models identify fixed and modifiable risk factors with addictive effects on the incidence of CI-AKI, kidney failure requiring dialysis and mortality (see Table 1). Preexisting kidney impairment is the main risk factor for CI-AKI. A decreased vasodilatory response has been observed in the available

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Mehran_FINAL2.indd 99

Fixed Risk Factors Chronic kidney disease

Modifiable Risk Factors Hypotension

Diabetes mellitus

Anaemia

Congestive heart failure

Nephrotoxic drugs

Age Hypercholesterolaemia Female sex Periprocedural dehydration/ hypovolaemic states Pre procedural hyperglycaemia Contrast type and contrast volume

Diabetes and hypertension both contribute to CKD. Even in the absence of clinically diagnosed CKD, endothelial dysfunction with reduced production of NO and vasoconstriction of vasa recta can be observed in patients with hypertension and diabetes and can contribute to the development of CI-AKI.29 Furthermore, preprocedural hyperglycaemia in patients without diabetes has been associated with higher rates of CI-AKI.30 The mechanism involved is based on the regional glucose catabolism that increases lactate concentration in the renal medulla and consequently promotes acidosis and production of ROS upon CM administration. When present, CKD with a cut-off value of GFR <60 ml/min/1.73 m2 is the strongest predictor of CI-AKI in diabetic patients. Incidence of CI-AKI after coronary angiography has been reported to be around 16 % in patients with diabetes and preserved renal function but it reaches 38 % in diabetic patients with CKD. In addition, in patients with CKD and diabetes, CI-AKI is a strong independent predictor of a 1-year mortality (OR 2.75; p<0.001).31 Other variables associated with higher rates of CI-AKI in diabetic patents are hypercholesterolaemia, contrast volume used >80 ml and insulin therapy.32 Conditions such as severe hypotension and CHF, particularly if requiring pressors or an intra-aortic balloon pump, can activate mechanisms of water reabsorption and concentrate CM in the tubules.25 In addition, activation of the renin-angiotensin-aldosterone axis causes vasoconstriction of kidney vessels that contributes to the ischaemic injury on the renal parenchyma. Similarly, anaemia generates a hyperdynamic circulation with peripheral vasoconstriction and higher risk of peripheral hypoxia.33 In animal models with CKD, anaemia seemed to promote damage of the renal proximal convoluted tubules and to reduce erythropoietin response to ischaemia. In vitro and in vivo studies have suggested erythropoietin might have pro-angiogenic and anti-apoptotic effects on endothelial

07/10/2016 00:12

Coronary Figure 1: Flowchart of Patient Risk Assessment and Management for Contrast-induced Acute Kidney Injury

Evaluation of patient risk of CI-AKI Mehran risk score

Low risk (< −5)

Intermediate risk (6–10)

High/very high risk (> −11)

CHF (5 points) Hypotension (5 points) Age >75 years (4 points) eGFR (4 points) DM (3 points) Anaemia (3 points) Contrast volume (1 point/100 cc)

Evaluate alternative procedures without CM Oral/IV hydration

Correct modifiable risk factors

• Treat/prevent periprocedural hypotension

• Correct anaemia • Suspend nephrotoxic drugs

Monitor creatinine daily or CrC/eGFR Avoid multiple procedures in 48–72 hours Periprocedural hydration with crystalloids 1–1.5 ml/kg/h 3–12 hours before and 12–24 hours after the procedure Prefer IOCM/LOCM Minimise volume of CM (CMV/CrC <3) N-Acetylcysteine 1200 mg twice daily/ascorbic acid 500 mg Periprocedural statin treatment (rosuvastatin)

CHF = Congestive heart failure; CI-AKI = contrast-induced acute kidney injury; CM = contrast media; CMV = contrast media volume; CrC = creatinine clearances; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; IOCM = iso-osmotic contrast media; IV = intravenous; LOCM = low-osmotic contrast media.

cells and promote renal functional recovery in models of hypoxic and ischaemic renal injury.33 In the presence of CKD and anaemia this protective mechanism might be impaired. In the clinical practice, it has been observed that a decrease in haematocrit of >6 % places patients, usually women, almost at double the risk of developing CI-AKI. Nephrotoxic drugs such as aminoglycosides, cyclosporin A, amphotericin, cisplatin and nonsteroidal anti-inflammatory drugs, undoubtedly favour the onset of CI-AKI. In addition, angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists can be a risk factor for CI-AKI.34 These drugs are very common among cardiac patients undergoing PCI, but when the GFR >60 ml/min/1.73 m2 their use rarely results in clinically relevant kidney damage upon exposure to CM. Conversely, in patients with CKD the synergistic effect of chronic use of ACE inhibitors and CM administration increases the risk of CI-AKI35 and might accelerate CKD progression. Patients’ age is strongly associated with the risk of CI-AKI. It is well known that with aging, the number of functioning nephrons in the kidney progressively decreases. In addition, older patients will frequently present most of the fixed risk factors described such as CKD, CHF, diabetes and hypertension. When analysed per age quartile and sex, the incidence of CI-AKI was similar between men and women in the youngest age cohorts. However, women had higher prevalence of CI-AKI compared with men in the 65- to 79-year-old (14.5 versus 11.0 %; p<0.001) and >80-year-old (18.7 versus 15.1 %; p=0.048) age groups. Adding to the age-related risk of CI-AKI, women usually have higher rates of anemia and CKD.36 According to Chen et al., stage 3 CKD is present in 74 % of women and 45 % of men at the time of admission for angiography.37

100

ICR_Mehran_FINAL2.indd 100

Preventive Measures Currently there is no specific treatment for CI-AKI once the injury has occurred, therefore it is critical to stratify the risk and implement all measures to prevent CI-AKI in selected patients. The main prophylactic strategies comprise: reduction of modifiable risk factors (anaemia, hypotension, use of nephrotoxic drugs), reduction of CM exposure and peri-procedural oral or intravenous hydration (see Figure 1). Additionally, treatment with acetylcysteine, ascorbic acid and statins has been evaluated over the years with discordant results.

Reduction of Contrast Media Volume and Contrast Selection Risk of CI-AKI depends directly on the volume of CM injected during the procedure and further increases in case of multiple staged interventions within 72 hours.38 Intra-arterial injection of CM, especially close to the renal arteries, is more frequently associated with CI-AKI than venous injection, probably because of the volumes used and the higher acute intrarenal concentrations. In the setting of primary PCI when few clinical and laboratory data are available before the procedure the ratio of contrast media volume (CMV) used to the estimated creatinine clearance (CMV/CrC) has been validated as an independent predictor of CI-AKI. The cut-off value varies depending on the study. Lanky et al. have reported a cut-off for CMV/CrC of 3.7,39 while Oreto et al. suggested a cut-off of 2.5.40 Gurm et al. observed an increased risk of CI-AKI and nephropathy requiring dialysis when CMV/CrC exceeded 2 and the risk became strongly significant when the ratio reached 3. As a general rule CM volume should be restricted accordingly to twice or thrice the eGFR. In patients with signiﬁcant renal impairment (stage 3 CKD or higher), 30 ml of contrast for diagnostic catheterisation, and 100 ml in case of PCI would be a reasonable target. In all patients, the maximal

INTERVENTIONAL CARDIOLOGY REVIEW

07/10/2016 00:12

Contrast‐induced Renal Failure

acceptable contrast dose (MACD), defined as 5 ml × body weight (kg)/ baseline serum creatinine (mg/dl) should not be exceeded.41 The introduction of automated injection devices that allow the operator to set a maximum dose of CM delivered with any injection has greatly reduced the total volume of contrast used during coronary angiography and PCI.42 In addition, expansion of new imaging modalities could be used to minimise the need for angiographic images and therefore reduce the CMV injected. Optical coherence tomography (OCT) has been reported as a useful tool to guide PCI. However, since CM injection is required during each acquisition, despite its advantages for vessel visualisation, OCT use might not result in a significant reduction of CM. Recently, the Minimizing cOntrast utiliZation With IVUS Guidance in coRonary angioplasTy (MOZART) trial has tested the use of IVUS to guide PCI and reduce CMV exposure. This study randomised 83 patients to angiography-guided PCI or IVUS guided PCI. For patients in the latter group, operators were encouraged to use IVUS to the limit of its potential in order to minimise acquisition of angiographic images. Results showed that use of IVUS to guide PCI is safe and significantly reduces the CMV used up to 3 folds compared to controls. Although the trial was not powered to detect changes in post-PCI renal function, a trend towards reduction of CI-AKI events was observed.43 Selection of the type of CM is also very important. Most hyperosmolar CM have demonstrated similar dose-dependent pro-apoptotic effects on endothelial cells in vitro and are currently now no longer used in most countries. Conversely, low-osmolar contrast media (LOCM) and iso-osmolar contrast media (IOCM) are less nephrotoxic and are strongly recommended in clinical practice guidelines especially for patients with prior renal dysfunction.22,44 A recent meta-analysis by Dong et al. including 3,129 patients, showed that the IOCM iodixanol significantly decreased the risk of CI-AKI compared with a pool of LOCM (iopromide, iopamidol, iohexol, ioversol, ioxaglate and iomeprol) when CM was injected intra-arterially.45 Conversely, a large meta-analysis including 36 randomised controlled trials did not find a statistically significant reduction in biochemical CI-AKI for IOCM compared with all LOCM agents (pooled OR 0.77; 95 % CI [0.56–1.06]; p=0.11). However, a benefit in terms of reduced CI-AKI incidence was found when comparing the IOCM iodixanol to one specific LOCM, iohexol (pooled OR 0.25; 95 % CI [0.11–0.55]).46 Importantly, in the Ionic versus non-ionic Contrast to Obviate worsening Nephropathy after angioplasty in chronic renal failure patients (ICON) trial, when tested against another LOCM, iodixanol did not reduce renal deterioration in patients with preexisting renal impairment.47

Peri-procedural Hydration Peri-procedural administration of intravenous fluids remains the cornerstone treatment for the prevention of CI-AKI in all patients.48 Volume expansion increases urine filtration rate and reduces the concentration of CM in the tubular fluid. The timing, rate and duration of intravenous fluid administration for the prevention of CI-AKI is unclear.49 Operating centres often implement different protocols based on empirical experience. Current clinical practice guidelines and consensus statements recommend intravenous (IV) hydration with isotonic 0.9 % NaCl 1.0–1.5 ml/kg/h started 3–12 hours before the procedure and continued for 12–24 hours after the exposure to CM. In case of a same-day procedure, a faster hydration with 3 ml/kg/h can be used at least 1–3 hours before and 6 hours after the procedure.50,51 Recently, results from the Prevention of Contrast Renal Injury with Different Hydration Strategies (POSEIDON) trial showed that

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Mehran_FINAL2.indd 101

fluid administration guided by end diastolic left ventricular pressure seemed safe and effective.52 All patients in the POSEIDON trial received a bolus infusion at 3 ml/kg of 0.9 % NaCl for 1 hour before the procedure. Additionally, patients randomised to Left ventricular end-diastolic pressure (LVEDP)-guided hydration received 5 ml/kg/h, 3 ml/kg/h or 1.5 ml/kg/h of 0.9 % NaCl for LVEDP of <13, 13–18 mmHg, and >18 mmHg, respectively, for 4 hours after the procedure. All patients in the control group were hydrated at 1.5 ml/kg/h with 0.9 % NaCl for the same amount of time. The rate of CI-AKI was significantly lower in patients with LVEDP-guided hydration compared to control (6.7 [12/178] versus 16.3 % [28/172]; relative risk 0.41; 95 % CI [0.22–0.79]; p=0.005). At 30 days and 6 months after the index procedure, incidence of CI-AKI, all-cause mortality, myocardial infarction, or renal replacement therapy was significantly lower in the LVEDP-guided hydration group.53 In 2004, the use of isotonic sodium bicarbonate, instead of saline was reported to be associated with a reduced incidence of acute CI-AKI. This result was attributed to the alkalisation of the renal parenchyma with a potential reduction in ROS production. However, subsequent studies have failed to confirm the benefit of sodium bicarbonate over isotonic saline.53,54

N-acetylcysteine and Ascorbic Acid Since production of reactive oxygen species plays an important role in CI-AKI, use of antioxidant agents has been evaluated over the years. N-acetylcysteine (NAC) is a potent scavenger of ROS and improves endothelium-dependent vasodilation. In animal models of ischaemia-reperfusion injury, NAC significantly reduced kidney damage.55 However, contrasting results have been obtained in clinical studies testing NAC for the prevention of CI-AKI. The reason for this can probably be attributed to differences in the study population, the study design and the cut-off values used to determine CI-AKI. Importantly, NAC has poor bioavailability, around 10–20 %, due to first pass effect and has a half- life of about 5 hours.55 Therefore, early administration before the procedure is unlikely to result in a clinical benefit. In addition, daily drug dose and route of administration might explain the different results. Carbonell et al. have seen a beneficial effect with an intravenous dose of 600 mg twice a day whereas other studies using up to 2400 mg of oral NAC did not significantly reduce the rate of CI-AKI.56 However, a recent meta-analysis comprising 1916 patients treated with intravenous NAC failed to prove a clinical benefit of NAC use for the prevention of CI-AKI.57,58 Results from the recently started Prevention of Serious Adverse Events Following Angiography (PRESERVE) trial might provide further information on the use of NAC. This randomised double blind study will comprise 8,680 high risk patients undergoing angiography and it will test the efficacy of NAC versus placebo and sodium bicarbonate versus 0.9 % NaCl hydration.58 In the meantime, the use of NAC for the prevention of CI-AKI is not recommended in the 2011 AHA/ACC guidelines for PCI.50 However, since NAC is inexpensive and appears to be safe at the doses used for CI-AKI prevention, its use could be considered in intermediate-high risk patients despite the inconclusive evidence available. The 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines on acute kidney injury support the use of oral NAC, in combination with intravenous crystalloids in patients at risk for CI-AKI.59 Ascorbic acid has also been used in randomised clinical trials because of its antioxidant properties. In vitro and animal studies suggest that ascorbic acid may augment NO supply and reduce

101

07/10/2016 00:12

Coronary the oxidative stress in the renal tubules and peritubular capillaries thus reducing the extent of CI-AKI.60,61 Similar to NAC results on the efficacy of ascorbic acid in this setting have been discordant.61,62 Nevertheless, a meta-analysis by Sadat et al., analysing data from nine randomised clinical trials for a total of 1,536 subjects, showed that patients with preexisting CKD receiving peri-procedural ascorbic acid either intravenously or orally had a lower prevalence of CI-AKI compared to those treated with placebo.63 However, so far ascorbic acid is not mentioned as a preventive measure in the current KDIGO clinical practice guidelines.59

Statins Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are known to exert pleiotropic effects beyond cholesterol lowering. In particular, in vitro studies suggest statins have anti-inflammatory and antioxidant properties that could reduce production of ROS and avoid cell apoptosis after CM exposure. When tested in patients, a single high loading dose of atorvastatin 24 hours before CM exposure was sufficient to reduce the rate of CI-AKI in patients with diabetes or moderate CKD.64 Conversely, the Prevention of Radiocontrast-Medium-induced nephropathy using short term highdose simvastatin (PROMISS) trial, evaluating simvastatin use in patients with CKD, failed to prove an effect on the rate of CI-AKI.65 Subsequent studies, mostly testing different regimens of rosuvastatin treatment, obtained positive results. For instance, the Protective Effect of Rosuvastatin and Antiplatelet Therapy On contrast-induced acute kidney injury and myocardial damage in patients with Acute Coronary Syndrome (PRATO-ACS) trial has shown that high doses of rosuvastatin (40 mg loading dose + 20 mg maintenance dose) in patients undergoing PCI significantly reduced CI-AKI and the 30-day rate of cardiovascular and renal events comprising persistent renal damage and dialysis.66 Rosuvastatin seemed effective even when used for a short time. Zahng et al. described a reduction of CI-AKI and a composite of death, dialysis and worsened heart failure at 30 days in patients treated with peri-procedural rosuvastatin consisting of 10 mg daily starting 2 days before PCI and continued for 3 days after the procedure.67 Overall, recent meta-analyses support the use of statins for the prevention of CI-AKI.68–70 Current clinical practice guidelines do not yet reflect the recent results on the use of statins for CI-AKI. However, while AHA/ACC guidelines on the management of non ST-segment elevation myocardial infarction (NSTEMI) suggest starting statin treatment before hospital discharge, based on recent evidence from randomised clinical trials and meta-analysis, the use of peri-procedural statins seems reasonable in patients undergoing PCI especially if presenting with risk factors for CI-AKI.

Fenoldopam Mesylate Fenoldopam mesylate is a selective dopamine-1 receptor agonist that induces systemic and regional vasodilation. Because of its quick mechanism of action, intravenous fenoldopam is approved by the US Food and Drug Administration for the treatment of urgent and emergent hypertension. In 2002, Tumulin et al. observed that fenoldopam prevented contrast-induced vasoconstriction of renal vessels thus significantly increasing renal blood flow. When tested on patients with CKD, intravenous fenoldopam resulted in a lower rate of CI-AKI compared to saline.71 Subsequently, a meta-analysis comprising 16 clinical trials for a total of over 1,200 patients showed a significant reduction of CI-AKI (OR 0.43; 95 % CI; [0.32–0.59]; P<0.001), need for

102

ICR_Mehran_FINAL2.indd 102

renal replacement therapy (OR 0.54; 95 % CI [0.34–0.84]; p=0.007), and in-hospital death (OR 0.64; 95 % CI [0.45–0.91]; p=0.01)72 with fenoldopam. Despite these promising results, larger randomised clinical trials on patients with CKD and CM exposure have failed to find any significant clinical benefit of fenoldopam use.73,74 Therefore, current KDIGO guidelines do not recommend the use of fenoldopam for the prevention of CI-AKI.59

Theophylline Since an increase in serum and urinary adenosine has been observed after CM administration in CI-AKI patients, treatment with theophylline, a non-specific adenosine receptor antagonist, has been evaluated. Although a mild nephroprotective effect has been observed in a few clinical trials, the potential cardiovascular side effects and its interactions with numerous drugs currently limit the use of theophylline in the clinical practice.75

Renal Replacement Therapy Renal replacement therapies (RRT) with haemodialysis (HD) or continuous renal therapy (CRRT) have been evaluated as periprocedural prophylactic measures to prevent CI-AKI in patients at risk. However, clinical studies have found no benefit of RRT for the prevention of CI-AKI in patients with stage 3 CKD.76 Nevertheless, RRT with HD or CRRT could be considered only for patients with stage 4–5 CKD who are not on periodic haemodialysis. Approximately 3 % of patients with CKD develop severe AKI requiring dialysis. In these patients, RRT could reduce in hospital stay length and mortality.77

Current Clinical Practice Guidelines KDIGO are international evidence-based clinical practice guidelines published in 2012 that comprise current recommendations on the prevention and management of AKI.59 These guidelines include a comprehensive section on CI-AKI that gathers, expands and updates indications on this subject, previously available in interventional cardiology guidelines on the management of coronary artery disease. Acceptable definitions of CI-AKI have been expanded in the 2012 KDIGO document and now comprise an increase in serum creatinine (SCr) by ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours or an increase in SCr to ≥1.5-times baseline within 7 days, or a urine volume <0.5 ml/kg/h for 6 hours after contrast exposure. Importantly, the cut-off values for SCr and eGRF to identify patients at risk of CI-AKI are a baseline SCr concentration ≥1.3 mg/dl (≥115 μmol/l) in men and ≥1.0 mg/dl (≥88.4 μmol/l) in women, equivalent to an eGFR of <60 ml/min/1.73 m2. Consistent with AHA/ACC guidelines on percutaneous coronary interventions,50 reduction of the CM volume used and selection of either iso-osmolar or low-osmolar iodinated contrast media are strongly advised. Among the preventive measures listed in this review, KDIGO suggests the use of oral NAC, together with intravenous isotonic crystalloids, in patients at increased risk of CI-AKI. However, as previously mentioned, use of theophylline, fenoldopam and prophylactic IHD or haemofiltration are not recommended for the prevention of CI-AKI. Finally, although discussed in the KDIGO guidelines, there is no explicit recommendation regarding the use of ascorbic acid and statins.59 While evidence on ascorbic acid is still controversial, we believe it would be reasonable and safe to adopt a peri-procedural treatment strategy with statins for the prevention of CI-AKI in selected patients at risk based on the promising results of recent randomised clinical trials.

INTERVENTIONAL CARDIOLOGY REVIEW

07/10/2016 00:12

Contrast‐induced Renal Failure

Conclusion CI-AKI in patients with preexisting renal damage or risk factors for the development of kidney dysfunction is a potentially serious complication after angiographic procedures with increased short and long-term morbidity and mortality. Appropriate management

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

Morabito S, Pistolesi V, Benedetti G, et al. Incidence of contrast-induced acute kidney injury associated with diagnostic or interventional coronary angiography. J Nephrol 2012;25 :1098–107. DOI: 10.5301/jn.5000101; PMID: 22383347 Newhouse JH, Kho D, Rao QA, Starren J. Frequency of serum creatinine changes in the absence of iodinated contrast material: implications for studies of contrast nephrotoxicity. Am J Roentgenol 2008;191 :376–82. DOI: 10.2214/AJR.07.3280; PMID: 18647905 Caixeta A, Nikolsky E, Mehran R. Prevention and treatment of contrast-associated nephropathy in interventional cardiology. Curr Cardiol Rep 2009;11 :377–83; PMID: 19709498 Giacoppo D, Madhavan MV, Baber U, et al. Impact of contrast-induced acute kidney injury after percutaneous coronary intervention on short- and long-term outcomes: pooled analysis from the HORIZONS-AMI and ACUITY trials. Circ Cardiovasc Interv 2015;8 :e002475. DOI: 10.1161/ CIRCINTERVENTIONS.114.002475; PMID: 26198286 Toprak O, Cirit M, Yesil M, et al. Impact of diabetic and pre-diabetic state on development of contrast-induced nephropathy in patients with chronic kidney disease. Nephrol Dial Transplant 2007;22 :819–26; PMID: 17090607 6. Calvin AD, Misra S, Pflueger A: Contrast-induced acute kidney injury and diabetic nephropathy. Nat Rev Nephrol 2010;6 :679–88. DOI: 10.1038/nrneph.2010.116; PMID: 20877303; PMCID: PMC4476402 Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002;105 :2259–64. PMID: 12010907 From AM, Bartholmai BJ, Williams AW, et al. Mortality associated with nephropathy after radiographic contrast exposure. Mayo Clin Proc 2008;83 :1095–100. DOI: 10.4065/83.10.1095; PMID: 18828968 Weisbord SD, Chen H, Stone RA, et al. Associations of increases in serum creatinine with mortality and length of hospital stay after coronary angiography. J Am Soc Nephrol 2006;17 :2871–7. PMID: 16928802 Dangas G, Iakovou I, Nikolsky E, et al. Contrast-induced nephropathy after percutaneous coronary interventions in relation to chronic kidney disease and hemodynamic variables. Am J Cardiol 2005;95 :13–9. PMID: 15619387 James MT, Ghali WA, Tonelli M, et al. Acute kidney injury following coronary angiography is associated with a longterm decline in kidney function. Kidney Int 2010;78: 803–9. DOI: 10.1038/ki.2010.258; PMID: 20686453 Solomon RJ, Mehran R, Natarajan MK, et al. Contrast-induced nephropathy and long-term adverse events: cause and effect? Clin J Am Soc Nephrol 2009;4 :1162–9. DOI: 10.2215/ CJN.00550109; PMID: 19556381; PMCID: PMC2709519 Goldenberg I, Chonchol M, Guetta V. Reversible acute kidney injury following contrast exposure and the risk of long-term mortality. Am J Nephrol 2009;29 :136–44. DOI: 10.1159/000151772; PMID: 18753738 Brown JR, Malenka DJ, DeVries JT, et al. Transient and persistent renal dysfunction are predictors of survival after percutaneous coronary intervention: insights from the Dartmouth Dynamic Registry. Catheter Cardiovasc Interv 2008;72 :347–54. DOI: 10.1002/ccd.21619; PMID: 18729173 Tumlin J, Stacul F, Panel CINCW, et al. Pathophysiology of contrast-induced nephropathy. Am J Cardiol 2006;98 : 14K–20K. PMID: 16949376 Sendeski M, Patzak A, Pallone TL, et al. Iodixanol, constriction of medullary descending vasa recta, and risk for contrast medium-induced nephropathy. Radiology 2009;251 :697–704. DOI: 10.1148/radiol.2513081732; PMID: 19366904; PMCID: PMC2687533 Solomon R. Contrast-induced acute kidney injury (CIAKI). Radiol Clin North Am 2009;47 :783–8. DOI: 10.1016/ j.rcl.2009.06.001; PMID: 19744593 Wong PC, Li Z, Guo J, Zhang A. Pathophysiology of contrastinduced nephropathy. Int J Cardiol 2012;158 :186–92. DOI: 10.1016/j.ijcard.2011.06.115; PMID: 21784541 Heinrich MC, Kuhlmann MK, Grgic A, et al. Cytotoxic effects of ionic high-osmolar, nonionic monomeric, and nonionic isoosmolar dimeric iodinated contrast media on renal tubular cells in vitro. Radiology 2005;235 :843–9. PMID: 15845795 Seeliger E, Lenhard DC, Persson PB. Contrast media viscosity versus osmolality in kidney injury: lessons from animal studies. Biomed Res Int 2014;2014 :358136. DOI: 10.1155/2014/358136; PMID: 24707482; PMCID: PMC3950904 Hardiek K, Katholi RE, Ramkumar V, Deitrick C. Proximal tubule cell response to radiographic contrast media. Am J Physiol Renal Physiol 2001;280 :F61–70. PMID: 11133515 Peer A, Averbukh Z, Berman S, et al. Contrast media augmented apoptosis of cultured renal mesangial, tubular, epithelial, endothelial, and hepatic cells. Invest Radiol

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Mehran_FINAL2.indd 103

of patients at risk is crucial for the prevention of CI-AKI. Although a specific treatment for CI-AKI is not available removal of modifiable risk factors and implementation of periprocedural measures such as CM reduction and intravenous hydration can significantly lower the risk of CI-AKI in selected patients. n

2003;38 :177–82. PMID: 12595799 23. Quintavalle C, Brenca M, De Micco F, et al. In vivo and in vitro assessment of pathways involved in contrast media-induced renal cells apoptosis. Cell Death Dis 2011;2 :e155. DOI: 10.1038/cddis.2011.38; PMID: 21562587; PMCID: PMC3122117 24. Ueda J, Nygren A, Hansell P, Ulfendahl HR. Effect of intravenous contrast media on proximal and distal tubular hydrostatic pressure in the rat kidney. Acta Radiol 1993;34 :83–7. PMID: 8427755 25. Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol 2004;44 :1393–9. PMID: 15464318 26. Brown JR, DeVries JT, Piper WD, et al. Northern New England Cardiovascular Disease Study G: Serious renal dysfunction after percutaneous coronary interventions can be predicted. Am Heart J 2008;155 :260–6. DOI: 10.1016/j.ahj.2007.10.007; PMID: 18215595 27. Basile DP, Anderson MD, Sutton TA. Pathophysiology of acute kidney injury. Compr Physiol 2012;2 :1303–53. DOI: 10.1002/ cphy.c110041; PMID: 23798302; PMCID: PMC3919808 28. Toprak O. Chapter 10: Coronary angiography and contrastinduced nephropathy. In: Advances in the Diagnosis of Coronary Atherosclerosis. Edited by Suna F. Croatia: InTech, 2011;181–202. 29. Cheng H, Harris RC. Renal endothelial dysfunction in diabetic nephropathy. Cardiovasc Hematol Disord Drug Targets 2014;14 :22–33; PMID: 24720460; PMCID: PMC4657140 30. Stolker JM, McCullough PA, Rao S, et al. Pre-procedural glucose levels and the risk for contrast-induced acute kidney injury in patients undergoing coronary angiography. J Am Coll Cardiol 2010;55 :1433–40. DOI: 10.1016/j.jacc.2009.09.072; PMID: 20359592 31. Nikolsky E, Mehran R, Turcot D, et al. Impact of chronic kidney disease on prognosis of patients with diabetes mellitus treated with percutaneous coronary intervention. Am J Cardiol 2004;94 :300–5. PMID: 15276092 32. Pakfetrat M, Nikoo MH, Malekmakan L, et al. Comparison of risk factors for contrast-induced acute kidney injury between patients with and without diabetes. Hemodial Int 2010;14 :38–92. DOI: 10.1111/j.1542-4758.2010.00469.x; PMID: 20796046 33. Murakami R, Kumita S, Hayashi H, et al. Anemia and the risk of contrast-induced nephropathy in patients with renal insufficiency undergoing contrast-enhanced MDCT. Eur J Radiol 2013;82 :e521–4. DOI: 10.1016/j. ejrad.2013.06.004; PMID: 23827802 34. Peng F, Su J, Lin J, Niu W. Impact of renin-angiotensinaldosterone system-blocking agents on the risk of contrastinduced acute kidney injury: a prospective study and meta-analysis. J Cardiovasc Pharmacol 2015;65 :262–8. DOI: 10.1097/FJC.0000000000000189; PMID: 25502308 35. Cirit M, Toprak O, Yesil M, et al. Angiotensin-converting enzyme inhibitors as a risk factor for contrast-induced nephropathy. Nephron Clin Pract 2006;104 :c20–7; PMID: 16685140 36. Sidhu RB, Brown JR, Robb JF, et al. Interaction of gender and age on post cardiac catheterization contrast-induced acute kidney injury. Am J Cardiol 2008;102 :1482–6. DOI: 10.1016/ j.amjcard.2008.07.037; PMID: 19026300 37. Chen R, Kumar S, Timmis A, et al. Comparison of the relation between renal impairment, angiographic coronary artery disease, and long-term mortality in women versus men. Am J Cardiol 2006;97 :630–2; PMID: 16490426 38. Marenzi G, Assanelli E, Campodonico J, et al. Contrast volume during primary percutaneous coronary intervention and subsequent contrast-induced nephropathy and mortality. Ann Intern Med 2009;150 :170–7; PMID: 19189906 39. Laskey WK, Jenkins C, Investigators NDR, et al. Volume-tocreatinine clearance ratio: a pharmacokinetically based risk factor for prediction of early creatinine increase after percutaneous coronary intervention. J Am Coll Cardiol 2007;50 :584–90; PMID: 17692741 40. Ando G, de Gregorio C, Morabito G, et al. Renal functionadjusted contrast volume redefines the baseline estimation of contrast-induced acute kidney injury risk in patients undergoing primary percutaneous coronary intervention. Circ Cardiovasc Interv 2014;7 :465–72. DOI: 10.1161/ CIRCINTERVENTIONS.114.001545; PMID: 25027519 41. Gurm HS, Dixon SR, Smith DE, et al. Renal function-based contrast dosing to define safe limits of radiographic contrast media in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 2011;58 :907–14. DOI: 10.1016/j.jacc.2011.05.023; PMID: 21851878 42. Anne G, Gruberg L, Huber A, et al. Traditional versus automated injection contrast system in diagnostic and percutaneous coronary interventional procedures: comparison of the contrast volume delivered. J Invasive Cardiol 2004;16 :360–2. PMID: 15282428

43. Mariani J Jr, Guedes C, Soares P, et al. Intravascular ultrasound guidance to minimize the use of iodine contrast in percutaneous coronary intervention: the MOZART (Minimizing cOntrast utiliZation With IVUS Guidance in coRonary angioplasTy) randomized controlled trial. JACC Cardiovasc Interv 2014;7 :1287–93. DOI: 10.1016/j.jcin.2014.05.024; PMID: 25326742; PMCID: PMC4637944 44. Kushner FG, Hand M, Smith SC Jr, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009;54 :2205–41. DOI: 10.1016/j.jacc.2009.10.015; PMID: 19942100 45. Dong M, Jiao Z, Liu T, et al. Effect of administration route on the renal safety of contrast agents: a meta-analysis of randomized controlled trials. J Nephrol 2012;25 :290–301; DOI: 10.5301/jn.5000067; PMID: 22252847 46. From AM, Al Badarin FJ, McDonald FS, et al. Iodixanol versus low-osmolar contrast media for prevention of contrast induced nephropathy: meta-analysis of randomized, controlled trials. Circ Cardiovasc Interv 2010;3:351–8. DOI: 10.1161/CIRCINTERVENTIONS.109.917070; PMID: 20647563 47. Mehran R, Nikolsky E, Kirtane AJ, et al. Ionic low-osmolar versus nonionic iso-osmolar contrast media to obviate worsening nephropathy after angioplasty in chronic renal failure patients: the ICON (Ionic versus non-ionic Contrast to Obviate worsening Nephropathy after angioplasty in chronic renal failure patients) study. JACC Cardiovasc Interv 2009;2 :415–21. DOI: 10.1016/ j.jcin.2009.03.007; PMID: 19463464 48. Trivedi HS, Moore H, Nasr S, et al. A randomized prospective trial to assess the role of saline hydration on the development of contrast nephrotoxicity. Nephron Clin Pract 2003;93 :C29–34. PMID: 12411756 49. Nikolsky E, Mehran R. Hydration protocols to reduce the incidence of contrast-induced nephropathy. J Invasive Cardiol 2008;20 :527–38. PMID: 18829997 50. Levine GN, Bates ER, Blankenship JC, et al. Guideline for percutaneous coronary intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58 :e44–122. DOI: 10.1016/ j.jacc.2011.08.007; PMID: 22070834 51. McCullough PA. Contrast-induced acute kidney injury. J Am Coll Cardiol 2008;51 :1419–28. DOI: 10.1016/ j.jacc.2007.12.035; PMID: 18402894 52. Brar SS, Aharonian V, Mansukhani P, et al. Haemodynamicguided fluid administration for the prevention of contrastinduced acute kidney injury: the POSEIDON randomised controlled trial. Lancet 2014;383 :1814–23. DOI: 10.1016/ S0140-6736(14)60689-9; PMID: 24856027 53. Zapata-Chica CA, Bello Marquez D, Serna-Higuita LM, et al. Sodium bicarbonate versus isotonic saline solution to prevent contrast-induced nephropathy: a systematic review and meta-analysis. Colombia medica 2015;46: 90–103. 54. Brar SS, Hiremath S, Dangas G, et al. Sodium bicarbonate for the prevention of contrast induced-acute kidney injury: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2009;4 :1584–92. DOI: 10.2215/CJN.03120509; PMID: 19713291; PMCID: PMC2758263 55. Mehran R, Caixeta A. N-acetylcysteine in preventing contrastinduced nephropathy. To give, or not to give: that is the question. Rev Esp Cardiol 2010;63 :9–11. PMID: 20089220 56. Trivedi H, Daram S, Szabo A, et al. High-dose N-acetylcysteine for the prevention of contrast-induced nephropathy. Am J Med 2009;122 :874.e9–15. DOI: 10.1016/ j.amjmed.2009.01.035; PMID: 19699385 57. Sun Z, Fu Q, Cao L, et al. Intravenous N-acetylcysteine for prevention of contrast-induced nephropathy: a meta-analysis of randomized, controlled trials. PLoS One 2013;8 :e55124. DOI: 10.1371/journal.pone.0055124; PMID: 23383076; PMCID: PMC3559541 58. Weisbord SD, Gallagher M, Kaufman J, et al. Prevention of contrast-induced AKI: a review of published trials and the design of the prevention of serious adverse events following angiography (PRESERVE) trial. Clin J Am Soc Nephrol 2013;8 :1618–31. DOI: 10.2215/CJN.11161012; PMID: 23660180; PMCID: PMC3805082 59. KDIGO Work Group. clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012;2:122–123. DOI:10.1038/ kisup.2011.37 60. Rodrigues GJ, Lunardi CN, Lima RG, et al. Vitamin C improves the effect of a new nitric oxide donor on the vascular smooth muscle from renal hypertensive rats. Nitric Oxide 2008;18 :176–83. DOI: 10.1016/j.niox.2007.12.002;

103

07/10/2016 00:12

Coronary PMID: 18194676 61. McCullough PA, Akrawinthawong K. Ascorbic acid for the prevention of contrast-induced acute kidney injury. J Am Coll Cardiol 2013;62 :2176–7. DOI: 10.1016/ j.jacc.2013.07.066; PMID: 23994411 62. Brueck M, Cengiz H, Hoeltgen R, et al. Usefulness of N-acetylcysteine or ascorbic acid versus placebo to prevent contrast-induced acute kidney injury in patients undergoing elective cardiac catheterization: a single-center, prospective, randomized, double-blind, placebo-controlled trial. J Invasive Cardiol 2013;25 :276–83; PMID: 23735352 63. Sadat U, Usman A, Gillard JH, Boyle JR. Does ascorbic acid protect against contrast-induced acute kidney injury in patients undergoing coronary angiography: a systematic review with meta-analysis of randomized, controlled trials. J Am Coll Cardiol 2013;62 :2167–75. DOI: 10.1016/j. jacc.2013.07.065; PMID: 23994417 64. Quintavalle C, Fiore D, De Micco F, et al. Impact of a high loading dose of atorvastatin on contrast-induced acute kidney injury. Circulation 2012;126 :3008–16. DOI: 10.1161/ CIRCULATIONAHA.112.103317; PMID: 23147173 65. Jo SH, Koo BK, Park JS, et al. Prevention of radiocontrast medium-induced nephropathy using short-term high-dose simvastatin in patients with renal insufficiency undergoing coronary angiography (PROMISS) trial--a randomized controlled study. Am Heart J 2008;155 :499.e1–8. DOI: 10.1016/j.ahj.2007.11.042; PMID: 18294484 66. Leoncini M, Toso A, Maioli M, et al. Early high-dose rosuvastatin for contrast-induced nephropathy prevention in acute coronary syndrome: Results from the PRATO-ACS

104

ICR_Mehran_FINAL2.indd 104

67.

68.

69.

70.

71.

Study (Protective Effect of Rosuvastatin and Antiplatelet Therapy On contrast-induced acute kidney injury and myocardial damage in patients with Acute Coronary Syndrome). J Am Coll Cardiol 2014;63 :71–9. DOI: 10.1016/ j.jacc.2013.04.105; PMID: 24076283 Zhang J, Li Y, Tao GZ, et al. Short-term rosuvastatin treatment for the prevention of contrast-induced acute kidney injury in patients receiving moderate or high volumes of contrast media: a sub-analysis of the TRACK-D study. Chin Med J (Engl) 2015;128 :784–9. DOI: 10.4103/0366-6999.152620; PMID: 25758273; PMCID: PMC4833983 Marenzi G, Cosentino N, Werba JP, et al. A meta-analysis of randomized controlled trials on statins for the prevention of contrast-induced acute kidney injury in patients with and without acute coronary syndromes. Int J Cardiol 2015;183 :47– 53. DOI: 10.1016/j.ijcard.2015.01.046; PMID: 25662053 Ukaigwe A, Karmacharya P, Mahmood M, et al. Meta-analysis on efficacy of statins for prevention of contrast-induced acute kidney injury in patients undergoing coronary angiography. Am J Cardiol 2014;114 :1295–302. DOI: 10.1016/j. amjcard.2014.07.059; PMID: 25239829 Giacoppo D, Capodanno D, Capranzano P, et al. Meta-analysis of randomized controlled trials of preprocedural statin administration for reducing contrast-induced acute kidney injury in patients undergoing coronary catheterization. Am J Cardiol 2014;114 :541–8. DOI: 10.1016/j.amjcard.2014.05.036; PMID: 25001154 Tumlin JA, Wang A, Murray PT, Mathur VS. Fenoldopam mesylate blocks reductions in renal plasma flow after radiocontrast dye infusion: a pilot trial in the prevention of

contrast nephropathy. Am Heart J 2002;143 :894–903; PMID: 12040355 72. Landoni G, Biondi-Zoccai GG, Tumlin JA, et al. Beneficial impact of fenoldopam in critically ill patients with or at risk for acute renal failure: a meta-analysis of randomized clinical trials. Am J Kidney Dis 2007;49 :56–68. PMID: 17185146 73. Stone GW, McCullough PA, Tumlin JA, et al. Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomized controlled trial. JAMA 2003;290 :2284–91. PMID: 14600187 74. Allaqaband S, Tumuluri R, Malik AM, et al. Prospective randomized study of N-acetylcysteine, fenoldopam, and saline for prevention of radiocontrast-induced nephropathy. Catheter Cardiovasc Interv 2002;57 :279–83. PMID: 12410497 75. Dai B, Liu Y, Fu L, et al. Effect of theophylline on prevention of contrast-induced acute kidney injury: a meta-analysis of randomized controlled trials. Am J Kidney Dis 2012; 60 :360–70. DOI: 10.1053/j.ajkd.2012.02.332; PMID: 22516682 76. Song K, Jiang S, Shi Y, et al. Renal replacement therapy for prevention of contrast-induced acute kidney injury: a meta-analysis of randomized controlled trials. Am J Nephrol 2010;32 :497–504. DOI: 10.1159/000321344; PMID:20975263 77. Tasanarong A, Vohakiat A, Hutayanon P, Piyayotai D. New strategy of alpha- and gamma-tocopherol to prevent contrast-induced acute kidney injury in chronic kidney disease patients undergoing elective coronary procedures. Nephrol Dial Transplant 2013;28 :337–44. DOI: 10.1093/ndt/ gfs525; PMID: 23314316

INTERVENTIONAL CARDIOLOGY REVIEW

07/10/2016 00:12

Coronary

Fractional Flow Reserve Measurement by Computed Tomography: An Alternative to the Stress Test Ji Hy un Lee, 1 Bría in ó Ha rta ig h , 1 D o n g h e e H a n , 1 A s i m Ri z v i , 1 F a y Y L i n 1 ,2 a n d J a m e s K M i n 1,2 1. Dalio Institute of Cardiovascular Imaging, New York-Presbyterian Hospital, New York, NY, USA; 2. Departments of Radiology and Medicine, Weill Cornell Medical College, New York, NY, USA

Abstract Recent advances in computed tomographic technology have contributed towards improving coronary computed tomography angiography (CCTA) in determining the severity of coronary artery disease anatomically. Although the viability of CCTA has most often been confined to anatomical assessment, recent development has enabled evaluation of the haemodynamic significance of coronary artery disease. In light of this, CCTA-derived fractional flow reserve (FFRCT), a novel imaging modality, now permits the physiological assessment of coronary artery disease. To date, several studies have documented the diagnostic performance of FFRCT, and more trials are being performed that will further substantiate this technique. The present paper provides an overview and discussion of the available evidence for FFRCT in the clinical setting as well as potential future directions of FFRCT.

Keywords Coronary computed tomography angiography, coronary artery disease, fractional flow reserve, stress imaging test Disclosure: JKM has served as a consultant or on the medical advisory boards for GE Healthcare, HeartFlow Inc, and Arineta Ltd; and has received research support from GE Healthcare. JHL, BóH, DH, AR and FL have no conflicts of interest to declare. Acknowledgements: This study was supported by the National Institutes of Health (Bethesda, Maryland) under award numbers R01 HL111141 and R01 HL118019. This study was also funded, in part, by a generous donation from the Dalio Institute of Cardiovascular Imaging (New York, NY) and the Michael Wolk Foundation (New York, NY). Received: 18 December 2015 Accepted: 31 May 2016 Citation: Interventional Cardiology Review, 2016;11(2):105–9 DOI: 10.15420/icr.2016:1:2 Correspondence: James K Min, Weill Cornell Medical College, New York–Presbyterian Hospital, Dalio Institute of Cardiovascular Imaging, 413 E. 69th Street, Suite 108, New York, NY 10021, USA. E: jkm2001@med.cornell.edu

Coronary computed tomography angiography (CCTA) is a noninvasive tool capable of directly visualising the coronary anatomy with high sensitivity and negative predictive value (NPV) for coronary artery disease (CAD) compared to invasive coronary angiography (ICA).1,2 Recent innovations in computed tomography (CT) technology have led to the rapid development of CCTA and its selection as an anatomic alternative to stress imaging.3 Despite this, CCTA alone cannot independently determine the haemodynamic significance of coronary stenosis, as compared with stress imaging, due to the low specificity for identifying coronary stenoses that induce ischaemia.4 This emphasises the unpredictable relationship between stenosis severity and ischaemia, which may provoke the need for unnecessary ICA in patients who do not have ischaemia.5 For instance, patients undergoing CCTA with an intermediate lesion requiring ischaemia evaluation may have layers of additional testing, such as stress echocardiography, myocardial perfusion imaging by single-photon emission computed tomography, positron emission tomography or cardiac magnetic resonance image.6 Fractional flow reserve (FFR), defined as the ratio of maximum flow in a stenotic artery to maximum blood flow if the same artery were normal, is an invasive technique to determine lesion-specific ischaemia and can assist in guiding coronary revascularisation.7,8 Notably, in the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) trial, the use of FFR to guide coronary intervention compared with ICA guidance resulted in a 33 % reduction in major adverse cardiac

ICR_Min FINAL2.indd 105

events.9 Recent advances in computational fluid dynamics enable the calculation of CCTA-derived FFR (FFRCT) from three-dimensional imaging anatomic models. Foremost, FFRCT reflects a novel imaging modality with the ability to determine the haemodynamic significance of CAD without additional radiation exposure or contrast injection beyond the initial CCTA (see Figure 1). This review provides an overview of current evidence describing the appropriate use of FFRCT in the clinical setting, along with a discussion of the potential future directions of FFRCT.

Clinical Usefulness of FFR FFR has been utilised to assess physiological function at the time of ICA in the cardiac catheterisation laboratory. The former procedure provides a reliable physiological index for determining whether coronary stenosis may cause ischaemia by measuring flow with a coronary guidewire before and after a visualised stenosis during maximal hyperaemia.10 A common definition of FFR is the maximal blood flow to the myocardium in the presence of a stenosis in the supplying coronary artery divided by the theoretical normal maximal flow in the same distribution.7 In current guidelines, an FFR value ≤0.80 is widely considered the threshold for revascularisation. Numerous studies have confirmed the clinical benefit of utilising FFR in clinical practice.9,11–15 Revascularisation in the coronary arteries with a measured FFR of ≤0.80 was associated with improved prognosis, including a reduction in death rates, non-fatal myocardial infarction and urgent revascularisation when compared with ICA-

Access at: www.ICRjournal.com

105

07/10/2016 00:28

Coronary Figure 1: Example Case of Coronary Computed Tomography Angiography (CCTA) A

LAD

LCx

RCA

* *

A 69-year-old Caucasian man with exertional angina underwent CCTA. (A) Multiplanar reformat of CCTA demonstrates a severe stenosis in the proximal left anterior descending artery (LAD)*, a moderate stenosis in the middle of the LAD, and a moderate to severe stenosis in the proximal of the left circumflex artery (LCx) without specific lesion in the right coronary artery (RCA). (B) The coronary computed tomography angiography-derived fractional flow reserve (FFRCT) values of the LAD, LCx and RCA are 0.74, 0.66 and 0.91, respectively (normal >0.8). Values of the LAD and LCx indicate significant ischemia.

guided revascularisation alone or optimal medical therapy alone.16,17 Further still, Pijls et al. demonstrated in the DEFER trial that 5-year outcomes, and even 15-year outcomes, following deferral of percutaneous coronary intervention in the vessel of an intermediate coronary stenosis based on FFRs of ≥0.75 demonstrated excellent prognoses.11,18 In light of previous findings, current guidelines advocate a FFR-guided revascularisation strategy as a Class IA recommendation for identifying haemodynamically-relevant coronary lesions in stable patients, especially when non-invasive testing evidence of ischaemia is not available.19

Diagnostic and Clinical Performance of FFR CT To date, three prospective multicentre trials, namely the Diagnosis of Ischemia-Causing Stenoses Obtained via Non-invasive Fractional Flow Reserve (DISCOVER-FLOW),20 Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography (DeFACTO)21 and analysis of Coronary Blood Flow Using CT Angiography: Next Steps (NXT)22 studies, have evaluated the diagnostic performance of FFRCT compared with invasive FFR as a reference standard. These studies are summarised in Table 1. The DISCOVER-FLOW study was the first multicentre trial that assessed the diagnostic performance of FFRCT against ICA and invasive FFR. It included 103 patients with 159 measured coronary vessels from four

106

ICR_Min FINAL2.indd 106

sites in the United States, Europe and Asia.20 Anatomical obstruction was defined as a CCTA with stenosis ≥50 %, and either FFR ≤0.80 or FFRCT ≤0.80 was defined as ischaemia. In this study, both FFRCT and FFR correlated well on a per-vessel analysis according to Spearman’s rank correlation, reporting a coefficient of 0.72 (p <0.001). Further, utilising FFRCT on a per-vessel analysis revealed a diagnostic accuracy of 84.3 %, sensitivity of 87.9 %, specificity of 82.2 %, positive predictive value (PPV) of 73.9 %, and NPV of 92.2 %. The results did not differ materially on a per-patient analysis. Conversely, the accuracy, specificity and PPV were 58.5 %, 39.6 % and 46.5 %, respectively, based on a per-vessel analysis of CCTA; while a per-patient analysis demonstrated an accuracy of 61.2 %, specificity of 24.5 % and PPV of 58.0 %, respectively, according to CCTA. The area under the receiver operating characteristic curve (AUC) was 0.90 for FFRCT, which was superior to CCTA, which had an AUC of 0.75 (p=0.001), indicating a significant improvement in the discrimination of ischaemia. The DeFACTO trial included 252 patients across 17 centres in five countries with the measurement of 407 coronary vessels. It was conducted to determine the accuracy of FFRCT in comparison with invasive FFR as a gold standard for the diagnosis of haemodynamicallysignificant coronary stenosis.21 On a per-patient analysis, FFRCT was superior in detecting ischaemia when compared with CCTA according to diagnostic accuracy (73 versus 64 %), sensitivity (90 versus 84 %), specificity (54 versus 42 %), PPV (67 versus 61 %) and NPV (84 versus 72 %), respectively. In a patient-based analysis restricted to those presenting with intermediate stenosis (i.e. 30–70 % stenosis), sensitivity was significantly higher for FFRCT than for CCTA (82 versus 37 %), without a change in specificity. In addition, FFRCT displayed superior discrimination for ischaemia based on a per-patient as well as per-vessel analysis when compared with CCTA, with improved AUCs (0.81 versus 0.68 and 0.81 versus 0.75, respectively; p<0.001 for all). Though DeFACTO was unable to meet its pre-specified primary outcome, which was a per-patient diagnostic accuracy lower bound 95 % confidence interval no worse than 70 %, the utilisation of non-invasive FFRCT plus CT among stable patients demonstrated improved diagnostic accuracy as well as discrimination in comparison with CT alone for the diagnosis of haemodynamically-significant CAD.23 Most recently, the prospective multicentre NXT trial evaluated the diagnostic performance of FFRCT in 254 patients, with 484 vessels being studied.22 On a per-patient analysis, diagnostic accuracy, specificity and PPV were markedly higher for FFRCT (81 %, 79 % and 65 %, respectively) versus CCTA (53 %, 34 % and 40 %, respectively) (p<0.001, for all). Similarly, on a per-vessel analysis the accuracy, specificity and PPV were 86 %, 86 % and 61 %, respectively, for FFRCT compared with CCTA (65 %, 60 % and 33 %, respectively) (p<0.001, for all), without disparity in sensitivity (84 versus 83 %). In the same study, a subgroup analysis among patients with intermediate stenosis severity (i.e. 30–70 % stenosis) demonstrated that FFRCT was superior to CCTA on a per-patient level, with better accuracy (80 versus 51 %), specificity (79 versus 32 %) and PPV (63 versus 37 %) (p<0.001, for all) observed. Moreover, the AUCs for FFRCT on a per-patient and per-vessel basis were 0.90 and 0.93 versus 0.81 and 0.79 for CCTA, respectively (p<0.001 for all), indicating superior discrimination for ischaemia on the background of FFRCT. In summary, findings from the NXT multicentre trial support the contention that adding FFRCT to CCTA might provide a more comprehensive anatomical and physiological assessment of CAD.

INTERVENTIONAL CARDIOLOGY REVIEW

07/10/2016 00:28

Fractional Flow Reserve Measurement by Computed Tomography

Table 1: Summary of Diagnostic Accuracy Studies of Coronary Computed Tomography Angiography-derived Fractional Flow Reserve Study

Authors

(year)

N (sites)

Vessel

Reference

Size for

Standard

Diagnostic Performance (%)

Inclusion (fraction

(mm) flow

reserve)

Per-patient Analysis

Per-vessel Analysis

Sensitivity Specificity PPV NPV Sensitivity Specificity PPV NPV

DISCOVER-

Koo et al.

FLOW20

(2011)

DeFACTO21

Min et al.

103 (4)

≥2.0

≤0.80 93 81 85 91 88 82 74 92

252 (17)

≥1.5

≤0.80

251 (10)

≥2.0

≤0.80 86 79 65 93 84 86 61 95

67 84 83

– –

(2012) NXT22

Nørgaard

et al. (2014)

DISCOVER-FLOW = Diagnosis of Ischemia-Causing Stenoses Obtained Via Non-invasive Fractional FLOW Reserve; DeFACTO = Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography; NXT = Analysis of Coronary Blood Flow Using CT Angiography: Next Steps; PPV = positive predictive value; NPV = negative predictive value.

In previous studies, CT datasets were transferred so software applications could be run, and consequently hours of processing were required before the results were returned to the physician. To this end, recent studies have explored on-site prototype algorithms to compute FFR from CCTA, which in turn may enable a more efficient patient flow and reduce analysing time to within 1 hour.24–26 Among these studies, De Geer et al. demonstrated that the sensitivity, specificity, NPV, PPV and accuracy of FFRCT for detecting significant stenosis

dynamics approach to determine the FFR of three vessels from typically-obtained CCTA images without additional imaging, changes of image acquisition protocols, additional medication or radiation exposure.28 The computational fluid dynamics method enables the quantification of fluid pressure and velocity based on laws of mass conservation and momentum balance, while also solving the equations of human blood flow when applied to CCTA.

(FFR≤0.80) were 0.83, 0.76, 0.93, 0.56 and 0.78, respectively, on a perlesion basis, and displayed a Spearman rank correlation coefficient of 0.77 (p<0.001).26 Although still in its infancy, these investigators have strongly emphasised that this software permits on-site assessment of FFRCT within clinically-practical time frames, and may therefore have the necessary potential to be performed in a clinical setting.

Details regarding the steps involved in the calculation of FFRCT have been outlined previously,23 and are briefly described as follows: 1) the acquisition of CCTA and creation of patient-specific anatomical models; 2) the quantification of total and vessel-specific coronary flow; 3) the calculation of baseline microvascular resistance; 4) the computation of hyperaemic changes in coronary artery resistance; and 5) the application of computational fluid dynamics to calculate coronary flow, pressure and velocity during the stages of rest and hyperaemia. While it can take approximately 8 hours to calculate the results of FFRCT, the majority of FFRCT measurements can generally be calculated within a few hours, and it is anticipated that more advanced techniques in the field of FFRCT will eventually induce a substantial reduction in calculation time.

Recently, the Prospective Longitudinal Trial of FFRCT: Outcome and Resource Impacts (PLATFORM) trial compared a FFRCT-guided diagnostic strategy (n=297) with usual care (n=287) in 584 patients with new-onset chest pain and intermediate risk of CAD.27 Usual care was stratified by planned ICA or planned non-invasive testing prior to enrollment. In the planned ICA stratum (FFRCT-guided, n=193; usual care, n=187), ICA was cancelled in 61 % after receiving coronary CTA/FFRCT results, because the rate of non-obstructive CAD by ICA was 12.4 % (n=24) in the coronary CTA/FFRCT arm versus 73.3 % (n=137) in the usual care arm (p<0.001), with similar cumulative radiation exposure and 90 days clinical event rates. This result was similar after applying propensity score matching for 148 patients in each group (e.g. 12 % for CTA/FFRCT versus 72 % for usual care, P<0.001). In the planned non-invasive testing stratum (FFRCT-guided, n=104; usual care, n=100), the rate of non-obstructive CAD by ICA was comparable in both arms (12.5 versus 6.0 %; p=0.95). Overall, there was no significant difference in revascularisation in subjects allocated to CTA/FFRCT compared to usual care in either the planned non-invasive or planned invasive testing arms (p=0.29 and 0.58, respectively). The PLATFORM trial suggests that FFRCT may be a useful and safe gatekeeper to ICA, particularly for reducing the likelihood of normal ICA when used as an alternative diagnostic tool to guide care in patients with planned invasive catheterisation.

Principal Components for Determining FFR CT The scientific principles for determining FFRCT are described in detail elsewhere.28 In brief, FFRCT utilises a computational fluid

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Min FINAL2.indd 107

Further Study of FFR CT At present, studies related to FFRCT have mostly focused on its diagnostic performance for the determination of ischaemia, and comparisons of FFRCT with other stress imaging tests have not yet been implemented. To this end, several prospective multicentre clinical trials are currently on-going for the purpose of exploring the utility of FFRCT against other more established myocardial perfusion imaging procedures (see Table 2). The upcoming Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia (CREDENCE) trial aims to evaluate the direct comparison of coronary CTA plus FFRCT with MPI by SPECT or PET (NCT02173275). Moreover, two other multicenter trials, the Dual Energy CT for Ischemia Determination Compared to “Gold Standard” Non-Invasive and Invasive Techniques (DECIDE-Gold)29 and the comparison between stress cardiac computed tomography PERfusion versus Fractional flow rEserve measured by Computed Tomography angiography In the evaluation of suspected cOroNary artery disease (PERFECTION),30 aim to assess the diagnostic power of FFRCT as compared with single/dual-energy CT perfusion stress imaging testing. The results of these trials will undoubtedly spark further interest in the clinical utility of FFRCT.

107

07/10/2016 00:28

Coronary Table 2: On-going Prospective Multicentre Trials for Coronary Computed Tomography Angiography-derived Fractional Flow Reserve (FFR CT) Study

CREDENCE

618 Assessment of coronary computed

Study Objectives tomography angiography plus FFRCT versus myocardial perfusion imaging by single-photon emission computed tomography or positron emission tomography

PERFECTION

300 Assessment of FFRCT versus rest/stress single-energy computed tomography perfusion imaging

DECIDE-Gold29

156 Assessment of FFRCT versus rest/stress dual-energy computed tomography perfusion imaging

CREDENCE = Computed tomogRaphic Evaluation of atherosclerotic dEtermiNants of myocardial isChEmia; DECIDE-Gold = Dual Energy CT for Ischemia Determination Compared to ‘Gold standard’ non-invasive and invasive techniques; PERFECTION = comparison between stress cardiac computed tomography Perfusion Versus Fractional Flow Reserve Measured by Computed Tomography Angiography in the Evaluation of Suspected Coronary Artery Disease.

Current Limitations of FFR CT Despite the recent approval of FFRCT by the US Food and Drug Administration for routine use in patients without known CAD in the clinical setting, there remain several considerations relative to FFRCT that should be emphasised. Foremost, impaired image quality is capable of affecting the susceptibility of FFRCT. This infers that significant motion, beam-hardening from calcified lesions and artefacts from irregular breathing can affect image quality. Moreover, irregular and/or high heart rate, as well as a high body mass index, can further impair the quality of CT images. Further, several important factors are required to determine the accuracy of FFRCT, including the mathematical models related to coronary flow, lumen size, vessel resistance and potential variation in the hyperaemic response.6 To date, the extant literature has mostly focused on data from patients with an intermediate risk of CAD in contrast to those with a high pretest probability for whom performing ICA is typically mandatory in light of the time-consuming process of FFRCT. To this end, although the computation of FFRCT often takes several hours, forthcoming innovative iterations improve this limitation.23 At present, whether the impact of FFRCT is influenced by symptom typicality remains to be elucidated, and underlines the importance of future studies to examine the connection between FFRCT and symptom typicality. Although previous studies have demonstrated positive results in terms of diagnostic performance, we may add that FFRCT might not reliably reproduce the data obtained when using invasive FFR. To this end, the most recent NXT trial using the latest version of computational fluid dynamics demonstrated a PPV of only 65 % based on per-patient analysis. As such, additional studies are warranted to reliably determine the clinical performance of FFRCT for detecting significant lesion ischaemia. In 1.

Miller JM, Rochitte CE, Dewey M, et al. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med 2008;359 :2324–36. DOI: 10.1056/NEJMoa0806576; PMID: 19038879 Meijboom WB, Meijs MF, Schuijf JD, et al. Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study. J Am Coll Cardiol 2008;52 :2135–44. DIO: 10.1016/ j.jacc.2008.08.058; PMID: 19095130 Marwick TH, Cho I, Ó Hartaigh B, et al. Finding the gatekeeper to the cardiac catheterization laboratory: Coronary CT angiography or stress testing? J Am Coll Cardiol 2015;65: 2747–56. DOI: 10.1016/j.jacc.2015.04.060; PMID: 26112200 Meijboom WB, Van Mieghem CA, van Pelt N, et al.

108

ICR_Min FINAL2.indd 108

addition, the performance of FFRCT is not yet indicated in patients with a prior history of coronary artery bypass surgery or percutaneous coronary intervention with suspected in-stent restenosis. Forthcoming studies will advance our understanding through utilising further FFRCT development, including automated segmentation methods, machinelearning techniques and the refinement of the boundary conditions that underlie the FFRCT technology, thereby hopefully addressing the limitations of this method.23

Future Directions for FFR CT Several potential studies should be considered in future research that utilises FFRCT. Beyond improved diagnostic accuracy, FFRCT may enable improved guidance for clinical decision making. Importantly, further studies will assist in determining the role of FFRCT as a gatekeeper to cardiac catheterisation as well as its impact on cost and outcomes, thus building upon the near-term data brought to light by the PLATFORM trial.27 To this end, future studies such as the Assessing Diagnostic Value of Non-invasive FFRCT in Coronary carE (ADVANCE) study will investigate the clinical and economic impact of FFRCT as well as the potential reclassification of subjects with abnormal FFRCT for adverse cardiovascular outcomes.23 Determining the appropriate risk factors and CT characteristics for performing FFRCT remains a pressing issue for future research to address. Further, studies aimed at evaluating the cost-effectiveness of FFRCT should be considered. Hlatky et al. investigated the initial treatment costs from 96 patients in the DISCOVER-FLOW trial.31 In this study, the use of FFRCT for guiding the referral of patients for ICA and percutaneous coronary intervention reduced costs by 30 % (USD7,674 per patient) when compared with the most commonly used ICA/visual strategy (USD10,702 per patient), highlighting the potential value of FFRCT in a clinical setting. The performance of ‘virtual stenting’ is an emerging topic in the field of FFRCT. In this regard, the computational modelling required for FFRCT allows for the modification of coronary flow models. Moreover, Kim and colleagues documented a positive correlation between invasive FFR and FFRCT before and after stenting, while displaying a 96 % overall accuracy.32 In that study, the investigators demonstrated the feasibility of virtual coronary stenting of CT-derived computational models, suggesting this technology may prove useful for predicting functional outcomes after coronary revascularisation.

Conclusion FFRCT is a novel non-invasive technique for determining the haemodynamic significance of coronary artery stenosis. Prospective advances in FFRCT technology will assist in overcoming some of the current considerations associated with FFRCT. On-going prospective studies designed to compare the diagnostic power of FFRCT with other stress imaging tests will also offer clinicians an evidence-based alternative for detecting significant CAD, allowing for appropriate utilisation of FFRCT in the clinic. n

Comprehensive assessment of coronary artery stenoses: computed tomography coronary angiography versus conventional coronary angiography and correlation with fractional flow reserve in patients with stable angina. J Am Coll Cardiol 2008;52:636–43. DOI: 10.1016/j.jacc.2008.05.024; PMID: 18702967 Hachamovitch R, Di Carli MF. Methods and limitations of assessing new noninvasive tests: part I: Anatomy-based validation of noninvasive testing. Circulation 2008;117 : 2684–90. DOI: 10.1161/CIRCULATIONAHA.107.708586 Choi AD, Joly JM, Chen MY, et al. Physiologic evaluation of ischemia using cardiac CT: current status of CT myocardial perfusion and CT fractional flow reserve. J Cardiovasc Comput Tomogr 2014;8 :272–81. DOI: 10.1016/

j.jcct.2014.06.006; PMID: 25151919 Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334 :1703–8; PMID: 8637515 de Bruyne B, Bartunek J, Sys SU, et al. Simultaneous coronary pressure and flow velocity measurements in humans. Feasibility, reproducibility, and hemodynamic dependence of coronary flow velocity reserve, hyperemic flow versus pressure slope index, and fractional flow reserve. Circulation 1996;94 :1842–9; PMID: 8873658 Tonino PA, De Bruyne B, Pijls NH, et al. FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J

INTERVENTIONAL CARDIOLOGY REVIEW

07/10/2016 00:28

Fractional Flow Reserve Measurement by Computed Tomography

Med 2009;360 :213–24. DOI: 10.1056/NEJMoa0807611; PMID: 19144937 10. Pijls NH, De Bruyne B. Coronary pressure measurement and fractional flow reserve. Heart 1998;80 :539–42. PMC1728867 11. Pijls NH, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol 2007;49 :2105–11; PMID: 17531660 12. Fearon WF, Bornschein B, Tonino PA, et al. Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) Study Investigators. Economic evaluation of fractional flow reserve-guided percutaneous coronary intervention in patients with multivessel disease. Circulation 2010;122 : 2545–50. DOI: 10.1161/CIRCULATIONAHA.109.925396; PMID: 21126973 13. Li J, Elrashidi MY, Flammer AJ, et al. Long-term outcomes of fractional flow reserve-guided angiography-guided percutaneous coronary intervention in contemporary practice. Eur Heart J 2013;34 :1375–83. DOI: 10.1093/ eurheartj/eht005; PMID: 23344979 14. Park SJ, Ahn JM, Park GM, et al. Trends in the outcomes of percutaneous coronary intervention with the routine incorporation of fractional flow reserve in real practice. Eur Heart J 2013;34 :3353–61. DOI: 10.1093/eurheartj/eht404; PMID: 24092248 15. Van Belle E, Rioufol G, Pouillot C, et al. Investigators of the Registre Français de la FFR-R3F. Outcome impact of coronary revascularization strategy reclassification with fractional flow reserve at time of diagnostic angiography: insights from a large French multicenter fractional flow reserve registry. Circulation 2014;129 :173–85. DOI: 10.1161/ CIRCULATIONAHA.113.006646; PMID: 24255062 16. De Bruyne B, Pijls NH, Kalesan B, et al. FAME 2 Trial Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367 :991–1001. DOI: 10.1056/NEJMoa1205361; PMID: 22924638 17. De Bruyne B, Fearon WF, Pijls NH, et al. FAME 2 Trial Investigators. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med 2014;371 :1208–17. DOI: 10.1056/NEJMoa1408758; PMID: 25176289 18. Zimmermann FM, Ferrara A, Johnson NP, et al. Deferral vs. performance of percutaneous coronary intervention

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Min FINAL2.indd 109

19.

20.

21.

22.

23.

24.

25.

of functionally non-significant coronary stenosis: 15-year follow-up of the DEFER trial. Eur Heart J 2015;36 :3182–8. DOI: 10.1093/eurheartj/ehv452; PMID: 26400825 Windecker S, Kolh P, Alfonso F, et al. Authors/Task Force Members. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35 :2541–619. DOI: 10.1093/eurheartj/ehu278; PMID: 25173339 Koo BK, Erglis A, Doh JH, et al. Diagnosis of ischemiacausing coronary stenoses by noninvasive fractional flow reserve computed from coronary computed tomographic angiograms. Results from the prospective multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve) study. J Am Coll Cardiol 2011;58 :1989–97. DOI: 10.1016/ j.jacc.2011.06.066; PMID: 22032711 Min JK, Leipsic J, Pencina MJ, et al. Diagnostic accuracy of fractional flow reserve from anatomic CT angiography. JAMA 2012;308 :1237–45; PMID: 22922562 Nørgaard BL, Leipsic J, Gaur S, et al. NXT Trial Study Group. Diagnostic performance of noninvasive fractional flow reserve derived from coronary computed tomography angiography in suspected coronary artery disease: the NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps). J Am Coll Cardiol 2014;63 :1145–55. DOI: 10.1016/j.jacc.2013.11.043; PMID: 24486266 Min JK, Taylor CA, Achenbach S, et al. Noninvasive Fractional Flow Reserve Derived From Coronary CT Angiography: Clinical Data and Scientific Principles. JACC Cardiovasc Imaging 2015;8 :1209–22. DOI: 10.1016/j.jcmg.2015.08.006; PMID: 26481846 Renker M, Schoepf UJ, Wang R, et al. Comparison of diagnostic value of a novel noninvasive coronary computed tomography angiography method versus standard coronary angiography for assessing fractional flow reserve. Am J Cardiol 2014;114 :1303–8. DOI: 10.1016/j. amjcard.2014.07.064; PMID: 25205628 Coenen A, Lubbers MM, Kurata A, et al. Fractional flow reserve computed from noninvasive CT angiography data: diagnostic performance of an on-site clinician-operated

26.

27.

28.

29.

30.

31.

32.

computational fluid dynamics algorithm. Radiology 2015;274 :674–83. DOI: 10.1148/radiol.14140992; PMID: 25322342 De Geer J, Sandstedt M, Bjorkholm A, et al. Software-based on-site estimation of fractional flow reserve using standard coronary CT angiography data. Acta Radiol 2015. pii: 0284185115622075; PMID: 26691914: epub ahead of press Douglas PS, Pontone G, Hlatky MA, et al. PLATFORM Investigators. Clinical outcomes of fractional flow reserve by computed tomographic angiography-guided diagnostic strategies vs. usual care in patients with suspected coronary artery disease: the prospective longitudinal trial of FFRct: outcome and resource impacts study. Eur Heart J 2015;36 :3359–67. DOI: 10.1093/eurheartj/ehv444; PMID: 26330417 Taylor CA, Fonte TA, Min JK. Computational fluid dynamics applied to cardiac computed tomography for noninvasive quantification of fractional flow reserve: scientific basis. J Am Coll Cardiol 2013;61 :2233–41. DOI: 10.1016/ j.jacc.2012.11.083; PMID: 23562923 Truong QA, Knaapen P, Pontone G, et al. Rationale and design of the dual-energy computed tomography for ischemia determination compared to “gold standard” non-invasive and invasive techniques (DECIDE-Gold): A multicenter international efficacy diagnostic study of rest-stress dual-energy computed tomography angiography with perfusion. Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology 2015;22:1031–40. Pontone G, Andreini D, Guaricci AI, et al. Rationale and design of the PERFECTION (comparison between stress cardiac computed tomography PERfusion versus Fractional flow rEserve measured by Computed Tomography angiography In the evaluation of suspected cOroNary artery disease) prospective study. Journal of Cardiovascular Computed Tomography 2016. Hlatky MA, Saxena A, Koo BK, et al. Projected costs and consequences of computed tomography-determined fractional flow reserve. Clin Cardiol 2013;36 :743–8. DOI: 10.1002/clc.22205; PMID: 24114863 Kim KH, Doh JH, Koo BK, et al. A novel noninvasive technology for treatment planning using virtual coronary stenting and computed tomography-derived computed fractional flow reserve. JACC Cardiovasc Interv 2014;7 :72–8. DOI: 10.1016/j.jcin.2013.05.024; PMID: 24332418

109

07/10/2016 00:28

Coronary

Drug-coated Balloon-only Angioplasty for Native Coronary Disease Instead of Stents U pul Wi c k ra m a ra c h c h i a n d S i m o n E c c l e s h a l l Department of Cardiology, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK

Abstract Coronary angioplasty has vastly improved both in technique and devices since the first angioplasty in 1977. Currently, stent implantation is used almost ubiquitously, despite being developed originally to treat vessel threatening dissections. Newer concepts including absorbable polymers or fully bioabsorbable scaffolds are constantly being developed. However, we find the concept of no permanent implant whilst still delivering a chemotherapeutic drug to reduce restenosis very attractive given the long term implications of a metallic stent, which include restenosis, late thrombosis and neo-atheroma formation. The use of a drug-coated balloon-only approach to de novo angioplasty will avoid the late thrombotic problems whilst also reducing early restenosis, simplifying the procedure and reducing the dual antiplatelet duration to 1 month. We review the current literature and highlight our practice with regard to use of drug-coated balloons in treatment of de novo coronary artery disease.

Keywords Coronary angioplasty, de novo coronary artery disease, drug-coated balloon, drug-eluting stent Disclosure: The salary of UW (Clinical Research Fellow) is funded by the National Institute of Health Research via Research Capability Funding and an unrestricted research grant from B. Braun, Melsungen AG, Germany. SE receives speaker’s fees and acts as a consultant for B. Braun. Received: 31 May 2016 Accepted: 8 September 2016 Citation: Interventional Cardiology Review 2016;11(2):110–5 DOI: 10.15420/icr.2016:17:3 Correspondence: Simon Eccleshall, Department of Cardiology, Norfolk and Norwich University Hospital NHS Foundation Trust, Colney Lane, Norwich, NR4 7UY, UK. E: simon.eccleshall@nnuh.nhs.uk

Percutaneous coronary interventional techniques and devices have evolved enormously since Gruntzig performed his first coronary angioplasty in 1977.1 It is now the norm to treat patients with both acute coronary syndrome and stable coronary artery disease with drug-eluting stents. We intend to review the evidence and discuss potential benefits of drug-coated balloon-only angioplasty. These include return of original vasomotion, positive remodelling and avoiding stent-related complications such as stent under-expansion, malapposition, neo-atheroma, stent fracture, polymer/metal reactions and late/very late stent thrombosis. However, before we turn our attention to treatment of native coronary artery disease with drug-coated balloons, it is prudent to revisit history and understand what led to current practice.

Plain Old Balloon Angioplasty and Bare Metal Stents Interventional cardiologists who have been practicing long enough will remember the days of plain old balloon angioplasty (POBA) as challenging times. Acute complications such as acute vessel closure, flow-limiting dissections, acute recoil and vessel thrombosis as well as the medium term need for a second procedure due to restenosis were all troublesome. The introduction of bare metal stents (BMS) initially addressed the acute complications rather than the incidence of thrombosis and restenosis. Subsequently, the Belgian Netherlands Stent study (BENESTENT) and Stent Restenosis Study (STRESS) showed reduced restenosis rates with BMS compared with POBA (22 versus 32 % [p=0.02] and 31.6 versus 42.1 % [p=0.046], respectively).2,3 These studies drove a

110

Access at: www.ICRjournal.com

ICR_Eccleshall_FINAL2.indd 110

significant increase in use of BMS in the 1990s. In other words, the price to be paid to overcome the acute complications and reduce restenosis was a permanent metal implant. Interestingly, only 5.1 % (BENESTENT) and 6.9 % (STRESS) of patients from the angioplasty-only arm had to crossover to the stent group due to acute complications (i.e. acute vessel closure, flow-limiting dissection or a suboptimal angiographic result). So the question is, do all patients need a permanent metallic stent implant?

Drug-eluting Stents The TAXUS I-IV, Randomized Study with the Sirolimus-eluting Bx Velocity Balloon-expandable Stent (RAVEL) and Sirolimus-coated Bx Velocity Balloon-expandable Stent in the Treatment of Patients with De Novo Native Coronary Artery Lesions (SIRIUS) trials all showed benefits of DES over BMS in the reduction of target vessel revascularisations and restenosis rates.4–9 The Randomized Controlled Trial to Evaluate the Safety and Efficacy of the Medtronic AVE ABT-578 Eluting Driver™ Coronary Stent in De Novo Native Coronary Artery Lesions (ENDEAVOUR) trial programme as well as the Clinical Evaluation of the XIENCE V® Everolimus Eluting Coronary Stent System (SPIRIT II and III) studies showed the benefits of second generation DES over first generation DES.10–12 However, in-stent restenosis (ISR) and stent thrombosis continue to trouble both patients and interventionists, albeit at a lower rate, but with ever-increasing absolute numbers due to the increasingly widespread use of stents. In a 4-year follow-up of the Randomized, Twoarm, Non-inferiority Study Comparing Endeavor-Resolute Stent with Abbot Xience-V Stent (RESOLUTE-AC All-Comers) study, the patientoriented composite endpoint (all-cause death, myocardial infarction [MI] or any revascularisation) was 30.4 % and 28.6 %, respectively.13 We

07/10/2016 00:49

Drug-coated Balloon-only Angioplasty

feel these results should make the percutaneous coronary intervention (PCI) community consider alternative methods of revascularisation.

Table 1: Types of Paclitaxel-eluting Balloons and Coating Techniques Used

Bioresorbable Vascular Scaffolds

DCB Type

Excipient/Coating Technique

The argument that long-term outcomes should perhaps be more favourable when there is no permanent coronary implant has driven the development and implantation of bioresorbable vascular scaffolds (BVSs), with the scaffold being completely reabsorbed in approximately 4 years.14 In the ABSORB III Randomized Controlled Trial (ABSORB-III), scaffold thrombosis (1.5 %), target vessel MI and target vessel revascularisations (TVRs) were all higher than the second generation DES (but not statistically significant).15 The ISAR-ABSORB registry showed definite scaffold thrombosis of 2.6 % at 12 months follow-up.16 The early problems of scaffold implantation are still widely discussed and debated, but again we find these event rates high compared with existing treatment modalities.

SeQuent® Please (B. Braun Melsungen AG)

Iopromide matrix coating

Pantera Lux (BIOTRONIK AG)

BTHC matrix coating

IN.PACT Falcon™ (Medtronic)

FreePac™ matrix coating

DIOR® second generation (Eurocor)

Shellac matrix coating

Drug-coated Balloons Drug-coated balloons (DCBs) are standard (semi-compliant) angioplasty balloons coated with a cytotoxic chemotherapeutic agent. Currently, the majority of commercially available DCBs use paclitaxel. In our centre we predominantly use the balloon we feel has the best evidence (SeQuent® Please NEO, B. Braun Melsungen AG, Germany). This balloon utilises iopromide (a contrast medium) to act as the excipient to retain the drug on the balloon and, on balloon inflation, to facilitate rapid delivery to the vessel wall due to its lipophilicity. The dose of Paclitaxel is approximately 3 micrograms/mm2. The drug is delivered homogeneously to the vessel wall during balloon expansion (unlike the uneven distribution seen with drug-eluting stents). The terminal half-life is almost 2 months.17 There are different types of paclitaxel-coated balloons available in the market using different coating techniques and excipients (summarised in Table 1). A sirolimus coated balloon (SCB) has been introduced more recently with satisfactory bench testing and clinical outcomes.18 A registry of 277 patients with both de novo (55.42 %) and ISR (44.58 %) treated with SCB (Magic Touch™ balloon) has shown a major adverse cardiac event (MACE) rate of 5.38 % in the 186 patients who have undergone 12 months clinical follow-up so far (Transcatheter Cardiovascular Therapeutics [TCT] presentation, 2015).19 However, there are no formal angiographic follow-up data available as yet.

Potential Advantages of Not Having a Permanent Metal Implant Brodie et al. have published a long term longitudinal follow-up registry of 2,195 consecutive patients treated for ST elevation myocardial infarction (STEMI), comparing POBA to BMS and DES, and showed better long-term outcomes in the balloon angioplasty arm (POBA [n=601], stenting [n=1,594] from 1994 to 2010).20 Target vessel re-infarction and stent/lesion thrombosis were better with POBA compared with stents between 1 and 9 years (3.1 versus 7.9 % [p<0.001] and 2.9 versus 6.1 % [p=0.002], respectively; see Figure 1). Landmark analysis at 12 months showed a trend in favour of stenting with a non-significantly lower re-infarction rate only. It should be noted that there was no bail-out stent option in case of a vessel threatening complication (stents were only used from 1999 onwards outside of research procedures) and only single antiplatelet therapy was often used. In this cohort of balloon angioplasty cases only 23 % were discharged on thienopyridines. However, all patients received the standard treatment of the time. The authors concluded that there is a long term risk associated with a permanent coronary metallic implant.

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Eccleshall_FINAL2.indd 111

Elutax SV™ (Aachen Resonance)

No excipient

Lutonix® (Bard)

Polysorbate and Sorbitol carriers

Danubio (APR Medtech)

BTHC excipient

DCB = drug-coated balloon; BTHC = butyryl-tri-hexyl citrate.

A DCB-only strategy has the potential to overcome the long term complications of stent systems by avoiding a permanent implant, thus allowing the blood vessel to regain its original vasomotion and undergo positive remodelling. Togni et al. illustrated how stented segments do not undergo any vasodilatation during exercise, whilst those segments adjacent to sirolimus stents showed paradoxical vasoconstriction on exercise.21 Adverse effects of sirolimus stents on local endothelium dependent vasomotion have also been shown by Hofma et al.22 In contrast, whilst there is no published data on restoration of normal endothelial vasomotor function after DCB-only PCI, there is evidence of positive remodelling resulting in late luminal gain as shown by Kleber et al.23 This remodelling process is beneficial post DCB-PCI, but in the presence of a permanent metallic cage could result in late malapposition with subsequent late complications. The disadvantages of delayed endothelialisation, chronic inflammation, malapposition and under-expansion are all irrelevant when there is no permanent implant. The major difference between DCB and other treatment options is that the DCB option does not require even a temporary implant. Hence we suggest that a strategy which tackles the problem of restenosis whilst not involving a permanent metal stent or semi-permanent polymeric scaffold could be attractive in the vast majority of patients who undergo angioplasty when acute complications such as a flow-limiting dissection, vessel closure or recoil do not occur. It would be suitable in more than 90 % of patients undergoing angioplasty as shown in the BENESTENT and STRESS trials, but we do accept current PCI practice incorporates much more complex anatomy and techniques. We propose this is where DCB angioplasty has a role to play. It does not leave a permanent implant but targets restenosis with the delivery of a cytotoxic/cytostatic drug to the vessel wall. Obviously, DES and BVS will be necessary tools to have in the armoury in case of acute complications mentioned above.

Evidence for a Drug-coated Balloon-only Approach to De Novo Coronary Artery Disease Many early DCB studies (Paclitaxel Eluting Balloon Versus Drug Eluting Stent in Native Coronary Artery Stenoses of Diabetic Patients [PEPCAD IV], Paclitaxel-eluting Balloon Angioplasty and Coroflex™-Stents in the Treatment of Bifurcated Coronary Lesions [PEPCAD V], Drug-eluting Balloon in Acute Myocardial Infarction [DEB-AMI] and The Paclitaxeleluting Percutaneous Transluminal Coronary Angioplasty (PTCA) Balloon Catheter in Coronary Artery Disease to Treat Chronic Total Occlusions [PEPCAD CTO]) were carried out in conjunction with the implantation of a BMS, which in our view, takes away the long term advantages of a DCB-only/no permanent implant approach.24–27 We will therefore not discuss these further.

111

07/10/2016 00:49

Coronary

Number Entering Interval

601 1165 423

484 822 270

463 709 218

435 636 162

424 574 94

383 504 31

365 479

346 355

324 275

293 200

Years

May-15

Mar-15

Jan-15

Nov-14

0 Sep-14

Jul-14

BMS DES

3.00%

0.00%

BMS

May-14

6.00%

Jan-14

Log rank p-value BA versus DES = 0.21

Mar-14

9.00% Log rank p-value BA versus BMS = 0.27

Nov-13

DES

Sep-13

12.00%

Jul-13

Stent or lession thrombosis

Log rank p-value BA versus BMS = 0.016 Log rank p-value BA versus DES = 0.001

100

May-13

15.00%

Mar-13

Figure 2: Adoption Rate of Drug-coated Balloon (DCB)-only Angioplasty for One Operator Activity by number of vessels treated (%)†

Figure 1: Kaplan–Meier Estimates of Event Rates and Cardiac Mortality in Patients Treated with Drug-eluting Stents, Bare Metal Stents and Balloon Angioplasty for ST Segment Elevation Myocardial Infarction at a Single Centre Over 16 Years

Time (month, year) DCB Use †3-month

Stent Use

rolling average. Source: Data on file with corresponding author, Dr Simon Eccleshall.

B 15.00%

Target vessel reinfarction

Log rank p-value BA versus BMS = 0.001 Log rank p-value BA versus DES < 0.001 12.00%

DES

9.00% Log rank p-value BA versus BMS = 0.30 Log rank p-value BA versus DES = 0.65

6.00%

BMS

BA DES BMS

3.00%

0.00% Number Entering Interval

601 1165 423

482 820 257

461 707 214

431 633 157

421 570 90

386 500 30

364 434

345 351

322 270

281 196

Years

C 15.00%

Log rank p-value = 0.41 Stent

Cardiac mortality

12.00% Log rank p-value = 0.15 BA

9.00%

Stent 6.00%

3.00%

0.00%

421 567

396 465

376 379

353 291

323 213

Years Number Entering Interval

601 1594

511 1130

491 968

466 839

447 702

A: Stent or lesion thrombosis (ST/LT); B: target vessel re-infarction. Patients treated with both drug-eluting stent (DES) and bare metal stent (BMS) had greater frequency of ST/LT and target vessel re-infarction after 1 year compared with balloon angioplasty (BA). C: Kaplan– Meier estimates of cardiac mortality event rates at 0–1 year and >1 year in patients treated with stenting versus BA. Source: Brodie et al., 2014. Reproduced with permission from Wiley Periodicals, Inc © 2013. 20

There are a number of registries showing low event rates with DCB-only angioplasty in small vessel disease. The Paclitaxel-eluting PTCA-Balloon Catheter to Treat Small Vessel (PEPCAD I) study (82 patients with 2.25–2.80 mm vessel diameter treated with SeQuent Please) showed a MACE rate (composite of death, MI, target lesion revascularisation [TLR], treated lesion/stent thrombosis) of 6.1 % and

112

ICR_Eccleshall_FINAL2.indd 112

a TLR rate of only 4.9 % at 3-year follow-up.28 Zeymer U et al. in a real world prospective registry of 479 patients with small vessel disease (≥2.0 mm, ≤2.75 mm) treated with DCB angioplasty (SeQuent Please) showed a TLR rate of only 3.6 % at 9-month follow-up.29 There were no cardiac deaths. In the SeQuent Please worldwide all-comer registry, the DCB-only group (390 patients) showed event rates for MI 0.7 %, cardiac death 1.0 %, TVR 1.0 % and TLR 1.0 % at 9-month followup.30 The Elutax small vessel registry with 251 real world patients, 59 % of whom had native vessels treated with DCB angioplasty, showed a TLR rate of 2.0 %, cardiac death of 0.8 % and no target vessel MI or thrombosis at an average 225-days’ follow-up.31 Ho et al. reported TLR of 4 % at 9 months in a real world registry of 320 South-East Asian patients treated with SeQuent Please DCB (76 % de novo disease, 54 % small vessels and 76 % presented with acute coronary syndrome [ACS]).32 The single-arm, prospective, multicentre Valentines-II trial (103 patients, treated with second generation DIOR® DCB) showed a TLR rate of 2.9 %, a TVR of 6.9 % (including TLR), 1.0 % MI and 0.0 % cardiac death at 7.5 months.33 The Leipzig Prospective Drug-Eluting Balloon-Registry reported 76 patients treated with a DCB-only (SeQuent Please) for native coronary artery disease with no TLR at 2 years.34 The incidence of MI was 3.9 % with nine deaths (all-causes) during follow-up. It is important to note that most of these registries were real life studies, which included patients from high risk categories such as post-STEMI, non-ST segment elevation myocardial infarction (NSTEMI) and bifurcation lesions. The Paclitaxel-coated Balloon Versus Drug-eluting Stent During PCI of Small Coronary Vessels, a Prospective Randomised Clinical Trial (PICCOLETO) study showed a higher percentage diameter stenosis (43.6 versus 24.3 %; p=0.029) and higher restenosis rates (32.1 versus 10.3 %; p=0.043) in the DCB (first generation DIOR) treated arm compared with the paclitaxel-eluting stent (PES) arm in 60 patients with small vessel disease at 6 month angiography and 9-month clinical follow-up.35 It should be noted that first generation DIOR balloons have shown lower delivery of drug to the vessel wall. The roughened surface coating technique of this balloon was shown to be inferior to matrix coating in achieving neointimal suppression.36 Furthermore, 75 % of patients of the DCB arm did not have any predilatation done and 35 % of DCB patients had a BMS implanted, further impacting on the outcome of the technique.

INTERVENTIONAL CARDIOLOGY REVIEW

07/10/2016 00:49

Drug-coated Balloon-only Angioplasty

Figure 3: Case Example of a Left Anterior Descending/First Diagonal Bifurcation Lesion Treated with Drug-coated Balloon and Angiographic Follow-up at 4 Months

Figure 4: Case Example of a Chronic Total Occlusion of Right Coronary Artery Involving a Previous Stent Recanalised by Antegrade Approach, Treated with a Single Drug-coated Balloon and Follow-up Angiographic Appearance at 4 Months

A 73-year-old man presented with a (A) left anterior descending/first diagonal bifurcation lesion. The patient was treated with two drug-coated balloons with a final kiss. (B) A stent-like result is seen at 4-month follow-up.

The randomised controlled multicentre Balloon Elution and Late Loss Optimization (BELLO) study (total of 180 patients) showed better outcomes of DCB-only (IN.PACT Falcon™ [Medtronic]) treatment as compared with PES for vessels with a diameter of less than 2.8 mm.37 The primary endpoint of in-stent (or ’in-balloon’) late loss was significantly less with DCB compared with PES (0.08 ± 0.38 versus 0.29 ± 0.44 mm [difference -0.21]; 95 % CI [-0.34–0.09]; p [noninferiority]<0.001; p [superiority]=0.001). Of note, bail-out stenting was required in 20 % of lesions in the DCB group. The Paclitaxel-eluting Percutaneous Coronary Angioplasty (PTCA)Balloon Catheter for the Treatment of Coronary Bifurcations (PEPCADBIF) trial randomised 64 patients with bifurcation lesions to DCB-only (SeQuent Please) or POBA treatment and showed a binary restenosis rate of 6 versus 26 % (p=0.045), respectively at 9-month follow-up.38 Late luminal loss was significantly less with DCB-only treatment (0.13 mm in the DCB and 0.51 mm in the control POBA group; p=0.013;

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Eccleshall_FINAL2.indd 113

A 74-year-old man with a history of two coronary artery bypass grafts (first, early 1990s; second, 2013) and percutaneous coronary intervention to right coronary artery (RCA) and left circumflex artery, presented with limiting angina. (A) Pre-treatment angiographic appearance. The chronic total occlusion of RCA involving previous stent was recanalised by antegrade approach, predilated and finally treated with a single drug-coated balloon (DCB). A type C dissection was noted and left with no stent cover as there was Thrombolysis In Myocardial Infarction (TIMI) III flow. (B) Shows the result immediately following DCB-only angioplasty. (C) At 4-month follow-up the dissection was well healed and the result was excellent.

113

07/10/2016 00:49

Coronary Figure 5: Case Report of an Anterior ST Segment Elevation Myocardial Infarction Due to Distal Left Main Stem and Proximal Left Anterior Descending Disease Treated with a Single Drug-coated Balloon and Angiographic Follow-up at 4 Months

Cortese et al. have reported angiographic follow-up data at a mean 201 days post-procedure of 48 DCB (Restore [Cardionovum] and Elutax SV [Aachen Resonance]) treated patients, who had a type A-C dissection (18, 25 and five patients, respectively) left uncovered with a stent.40 Of these, 45 patients (93.8 %) had healed completely, three had persisting dissections and one received a DES follow-up. No cardiac death or other TLRs occurred in this group of patients with unstented dissections. This latter study highlights the issue of safe outcomes after balloon angioplasty-only despite the angiographic appearances of vessel dissection.

Technique To perform DCB-only PCI, care must be taken to prepare the lesion adequately before delivering the drug. Standard semi- and or noncompliant balloons, and if necessary, more specialised cutting or scoring balloons are used to achieve an adequate angiographic result. Gentle predilatation is performed at a 1:1 balloon-to-vessel ratio with adequate pressure to achieve full balloon expansion rather than standard high pressure inflation. Then the final treatment is carried out using the DCB, which is kept expanded for 30–60 seconds. The concept of the DCB is to act as a drug delivery device only, not to perform further angioplasty. We generally follow the German consensus guidelines, which recommend a DCB-only strategy unless residual stenosis of more than 30 % or dissections of more than type B are present.41 If any of the above two are present, particularly in the context of less than thrombolysis in myocardial infarction (TIMI) III flow, we recommend bail-out stenting to be performed. Heavily calcific vessels may require rotablation to avoid balloon-induced major dissection, whilst aorto-ostial lesions can limit the utility of DCB-only PCI due to the higher incidence of recoil. Dual antiplatelet therapy is required for only 1 month after DCB-only elective procedures or 1 year for treatment of ACS.

A 46-year-old male smoker presented with an anterior ST elevation myocardial infarction (STEMI). His distal left main stem and ostial left anterior descending lesions were treated with a single drug-coated balloon after thrombus aspiration. Top: Pre-treatment; Bottom: At 4-month follow-up.

95 % CI [-0.66–0.08]), whilst the TLR rates were 3.12 % for DCB and 9.38 % for POBA (not statistically significant). In an abstract presented at EuroPCR in May 2016, Rosenberg et al. showed a TLR rate of only 2.3 % in 731 de novo lesions (vessel size of 2–4mm and lesion length of <25 mm) after 9 months clinical followup.39 This was a prospective, international, multicentre registry with a total of 1,025 patients with both de novo and ISR lesions.

Gruntzig A. Transluminal dilatation of coronary-artery stenosis. Lancet 1978;311 :263. DOI: http://dx.doi.org/10.1016/ S0140-6736(78)90500-7; PMID: 74678 Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med 1994;331 :489–95. DOI: 10.1056/NEJM199408253310801; PMID:8041413 Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994;

114

ICR_Eccleshall_FINAL2.indd 114

As with all procedures there is a learning curve in performing DCBonly angioplasty. Adoption rate varies from operator to operator based on their personal experience and exposure. We recommend a visit to a centre where DCB angioplasty is performed routinely to observe the procedure and carry out cases in conjunction with an experienced operator. Published here is the adoption rate of DCB-only angioplasty for one of the operators in our department (see Figure 2). Also published here are three illustrative case studies (see Figures 3–5).

Conclusion We believe the DCB-only approach for coronary interventions with use of DES/BVS only in bail-out situations (originally shown to be around 5–6 % of angioplasty patients as per the STRESS and BENESTENT trials) will lead to better short, medium and long-term outcomes based on these observations. A large, randomised trial comparing DCB to second generation DES in de novo coronary artery disease, with long-term follow-up is required to demonstrate these benefits further. n

331 :496–501. Grube E, Silber S, Hauptmann KE, et al. TAXUS I: Six- and Twelve-Month Results From a Randomized, Double-Blind Trial on a Slow-Release Paclitaxel-Eluting Stent for De Novo Coronary Lesions. Circulation 2003;107 :38–42. DOI: 10.1161/01.CIR.0000047700.58683.A1; PMID: 12515740 Colombo A, Drzewiecki J, Banning A, et al. Randomized study to assess the effectiveness of slow- and moderaterelease polymer-based paclitaxel-eluting stents for coronary artery lesions. Circulation 2003;108 :788–94. DOI: 10.1161/01. CIR.0000086926.62288.A6; PMID:12900339

Tanabe K, Serruys PW, Grube E, et al. TAXUS III Trial: in-stent restenosis treated with stent-based delivery of paclitaxel incorporated in a slow-release polymer formulation. Circulation 2003;107 (4):559–64. PMID:12566366 Stone GW, Ellis SG, Cox DA, et al. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: The TAXUS-IV trial. Circulation 2004;109 :1942–7. DOI: 10.1161/01.CIR.0000127110.49192.72; PMID:15078803 Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349 :1315–23. DOI: 10.1056/ NEJMoa035071; PMID:14523139

INTERVENTIONAL CARDIOLOGY REVIEW

07/10/2016 00:49

Drug-coated Balloon-only Angioplasty

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346 (23):1773–80. DOI: 10.1056/NEJMoa012843; PMID:12050336 Kandzari DE, Leon MB, Meredith I, et al. Final 5-year outcomes from the Endeavor zotarolimus-eluting stent clinical trial program: comparison of safety and efficacy with first-generation drug-eluting and bare-metal stents. JACC Cardiovasc Interv 2013;6 (5):504–12. DOI: 10.1016/j. jcin.2012.12.125; PMID:23602459 Serruys P, Ruygrok P, Neuzner J, et al. A randomised comparison of an everolimus-eluting coronary stent with a paclitaxel-eluting coronary stent: the SPIRIT II trial. EuroIntervention 2006;2 :286–94. PMID:19755303 Stone GW, Midei M, Newman W, et al. Comparison of an everolimus-eluting stent and a paclitaxel-eluting stent in patients with coronary artery disease: a randomized trial. JAMA 2008;299 :1903–13. DOI: 10.1001/jama.299.16.1903; PMID:18430909 Taniwaki M, Stefanini GG, Silber S, et al. 4-year clinical outcomes and predictors of repeat revascularization in patients treated with new-generation drug-eluting stents: a report from the RESOLUTE All-Comers trial (A Randomized Comparison of a Zotarolimus-Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention). J Am Coll Cardiol 2014;63 :1617–25. DOI: 10.1016/j.jacc.2013.12.036; PMID:24530680 Onuma Y, Serruys PW. Bioresorbable scaffold: the advent of a new era in percutaneous coronary and peripheral revascularization? Circulation 2011;123 :779–97. DOI: 10.1161/ CIRCULATIONAHA.110.971606; PMID:21343594 Ellis SG, Kereiakes DJ, Metzger DC, et al. Everolimus-Eluting Bioresorbable Scaffolds for Coronary Artery Disease. N Engl J Med 2015;373 (20):1905–15. DOI: 10.1056/NEJMoa1509038; PMID:26457558 Hoppmann P, Kufner S, Cassese S, et al. Angiographic and clinical outcomes of patients treated with everolimuseluting bioresorbable stents in routine clinical practice: Results of the ISAR-ABSORB registry. Catheter Cardiovasc Interv 2016;87 (5):822–9. DOI: 10.1002/ccd.26346; PMID:26708019 Speck U, Stolzenburg N, Peters D, Scheller B. How does a drug-coated balloon work? Overview about coating technologies and their impact. J Cardiovasc Surg (Torino) 2015; PMID:26681536: epub ahead of print. Sojitra P, Yazdani S, Otsuka F, et al. CRT-123 A Novel Nano Particle Sirolimus Delivery Via Coated Balloon. J Am Coll Cardiol Intv 2013;6 (2_S):S40–S40. DOI: 10.1016/j. jcin.2013.01.042 Dani SI. Novel nanocarrier sirolimus-coated balloon for coronary and peripheral application. 2015. Available at: www. nanolute.net/wp-content/uploads/2015/12/TCT-2015-SCBfor-coronary-and-peripherical-application.pdf (Accessed 9 September 2016). Brodie BR, Pokharel Y, Garg A, et al. Very late hazard with stenting versus balloon angioplasty for ST‐elevation

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Eccleshall_FINAL2.indd 115

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

myocardial infarction: a 16‐Year single‐center experience. J Interv Cardiol 2014;27 :21–8. DOI: 10.1111/joic.12082; PMID:24372979; PMCID:PMC3955946 Togni M, Windecker S, Cocchia R, et al. Sirolimus-eluting stents associated with paradoxic coronary vasoconstriction. J Am Coll Cardiol 2005;46 (2):231–6. DOI: 10.1016/j. jacc.2005.01.062; PMID:16022947 Hofma SH, van der Giessen WJ, van Dalen BM, et al. Indication of long-term endothelial dysfunction after sirolimus-eluting stent implantation. Eur Heart J 2006;27 (2):166–70. DOI: 10.1093/eurheartj/ehi571; PMID:16249221 Kleber FX, Schulz A, Waliszewski M, et al. Local paclitaxel induces late lumen enlargement in coronary arteries after balloon angioplasty. Clin Res Cardiol 2015;104 :217–25. DOI: 10.1007/s00392-014-0775-2; PMID:25349065 Ali RM, Degenhardt R, Zambahari R, et al. Paclitaxel-eluting balloon angioplasty and cobalt-chromium stents versus conventional angioplasty and paclitaxel-eluting stents in the treatment of native coronary artery stenoses in patients with diabetes mellitus. EuroIntervention 2011;7 Suppl K :K83–92. DOI: 10.4244/EIJV7SKA15; PMID:22027736 Mathey DG, Wendig I, Boxberger M, et al. Treatment of bifurcation lesions with a drug-eluting balloon: the PEPCAD V (Paclitaxel Eluting PTCA Balloon in Coronary Artery Disease) trial. EuroIntervention 2011;7 Suppl K :K61–5. DOI: 10.4244/ EIJV7SKA11; PMID:22027730 Belkacemi A, Agostoni P, Nathoe HM, et al. First results of the DEB-AMI (drug eluting balloon in acute ST-segment elevation myocardial infarction) trial: a multicenter randomized comparison of drug-eluting balloon plus bare-metal stent versus bare-metal stent versus drug-eluting stent in primary percutaneous coronary intervention with 6-month angiographic, intravascular, functional, and clinical outcomes. J Am Coll Cardiol 2012;59 (25):2327–37. DOI: 10.1016/j.jacc.2012.02.027; PMID:22503057 Wöhrle J, Werner GS. Paclitaxel-coated balloon with baremetal stenting in patients with chronic total occlusions in native coronary arteries. Catheter Cardiovasc Interv 2013;81 (5):793–9. DOI: 10.1002/ccd.24409; PMID:22511572 Unverdorben M, Kleber FX, Heuer H, et al. Treatment of small coronary arteries with a paclitaxel-coated balloon catheter in the PEPCAD I study: are lesions clinically stable from 12 to 36 months? EuroIntervention 2013;9 (5):620–8. DOI: 10.4244/ EIJV9I5A99; PMID:24058078 Zeymer U, Waliszewski M, Spiecker M, et al. Prospective ‘real world’ registry for the use of the ‘PCB only’ strategy in small vessel de novo lesions. Heart 2014;100 (4):311–6. DOI: 10.1136/heartjnl-2013-304881; PMID:24281754 Woehrle J, Motz W, Möbius-Winkler S, et al. Sequent please worldwide registry: Results of Paclitaxel coated balloon angioplasty for treatment of de-novo coronary artery disease. J Am Coll Cardiol 2012;59 (13s1):E57-E57. DOI: 10.1016/S07351097(12)60058-8 Cortese B, Fetiveau R, Carrera A, et al. TCT-417 Treatment of coronary artery disease with a new-generation drug-coated

balloon: preliminary results from the Italian Elutax SV Registry. J Am Coll Cardiol 2015;66(15_S). DOI: 10.1016/j.jacc.2015.08.431 32. Ho HH, Ooi YW, Loh KK, et al. Clinical Efficacy and Safety of SeQuent Please Paclitaxel-Eluting Balloon in a RealWorld Single-Center Registry of South-East Asian Patients. Int J Cardiol Heart Vessels 2013;1 :37–41. DOI: http://dx.doi. org/10.1016/j.ijchv.2013.11.008 33. Waksman R, Serra A, Loh JP, et al. Drug-coated balloons for de novo coronary lesions: results from the Valentines II trial. EuroIntervention 2013;9 (5):613–9. DOI: 10.4244/EIJV9I5A98; PMID:24058077 34. Uhlemann M, Möbius-Winkler S, Adam J, et al. The Leipzig Prospective Drug-Eluting Balloon-Registry - Outcome of 484 Consecutive Patients Treated for Coronary In-Stent Restenosis and De Novo Lesions Using Paclitaxel-Coated Balloons. Circ J 2016;80 (2):379–86. DOI: 10.1253/circj. CJ-14-1352; PMID:26632530 35. Cortese B, Micheli A, Picchi A, et al. Paclitaxel-coated balloon versus drug-eluting stent during PCI of small coronary vessels, a prospective randomised clinical trial. The PICCOLETO study. Heart 2010;96 (16):1291–6. DOI: 10.1136/hrt.2010.195057; PMID:20659948 36. Cremers B, Biedermann M, Mahnkopf D, et al. Comparison of two different paclitaxel-coated balloon catheters in the porcine coronary restenosis model. Clin Res Cardiol 2009;98(5):325–30. DOI: 10.1007/s00392-009-0008-2; PMID:19280084 37. Latib A, Colombo A, Castriota F, et al. A randomized multicenter study comparing a paclitaxel drug-eluting balloon with a paclitaxel-eluting stent in small coronary vessels: the BELLO (Balloon Elution and Late Loss Optimization) study. J Am Coll Cardiol 2012;60 (24):2473–80. DOI: 10.1016/j. jacc.2012.09.020; PMID:23158530 38. Kleber FX, Rittger H, Ludwig J, et al. Drug eluting balloons as standalone procedure for coronary bifurcational lesions: results of the randomized multicenter PEPCAD-BIF trial. Clin Res Cardiol 2016;105 :613–21. DOI: 10.1007/s00392-015-0957-6; PMID:26768146 39. Rosenberg M, Chin K, Bin Wan Ahmad W, et al. Prospective, large-scale multicentre trial for the use of paclitaxelcoated balloons in de novo coronary lesions: the PCBONLY all-comer registry.Abstracts EuroPCR 2016, May 2016. Available at: www.pcronline.com/eurointervention/ AbstractsEuroPCR2016_issue/abstracts-europcr-2016/ Euro16A-OP1057/prospective-large-scale-multicentretrial-for-the-use-of-paclitaxel-coated-balloons-in-de-novocoronary-lesions-the-pcb-only-all-comer-registry.html#sthash. scc6h5SF.dpuf (Accessed 9 September 2016). 40. Cortese B, Silva Orrego P, Agostoni P, et al. Effect of DrugCoated Balloons in Native Coronary Artery Disease Left With a Dissection. JACC Cardiovasc Interv 2015;8 (15):2003–9. DOI: 10.1016/j.jcin.2015.08.029; PMID:26627997 41. Kleber FX, Rittger H, Bonaventura K, et al. Drug-coated balloons for treatment of coronary artery disease: updated recommendations from a consensus group. Clin Res Cardiol 2013;102 (11):785–97. DOI: 10.1007/s00392-013-0609-7; PMID:23982467

115

07/10/2016 00:49

Coronary

The FAME Trials: Impact on Clinical Decision Making Gu y R H e y n d r i c k x 1 a n d G á b o r G Tó t h 2 1. Cardiovascular Center Aalst, OLV-Clinic, Aalst, Belgium; 2. University Heart Center, Medical University of Graz, Graz, Austria

Abstract Careful and stepwise evaluation of the fractional flow reserve (FFR) index has been performed over the years, culminating in the landmark Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) and Fractional Flow Reserve-Guided Percutaneous Coronary Intervention Plus Optimal Medical Treatment Versus Optimal Medical Treatment Alone in Patients with Stable Coronary Artery Disease (FAME II) trials. Findings from these studies demonstrated unequivocally the overall inadequacy of angiography versus FFR to correctly assess stenosis severity. Thus, proof of concept and clinical applicability was established beyond debate and will be discussed here.

Keywords Coronary artery disease, ischaemia, angiography, fractional flow reserve, FAME Disclosure: The authors have no disclosures to make that are relevant to the present article. Received: 2 May 2016 Accepted: 31 August 2016 Citation: Interventional Cardiology Review, 2016;11(2):116–9 DOI: 10.15420/icr.2016:14:3 Correspondence: Guy R Heyndrickx, Cardiovascular Center Aalst, OLV-Clinic, Moorselbaan, 164, B-9300 Aalst, Belgium. E: guy.heyndrickx@skynet.be

The presence as well as the extent of myocardial ischaemia are key to determining cardiovascular outcome,1–3 thus its identification is important. An endeavour to improve diagnostic accuracy in deciding which angiographic lesions are haemodynamically significant led to the development of the concept of fractional flow reserve (FFR). Based on pressure-flow analysis of a stenosis during maximum flow, the FFR indicates the impact of a coronary stenosis on the maximum inducible coronary flow and whether it would be susceptible to induce ischaemia during stress. In a landmark report, Pijls and co-workers validated the FFR index in a group of patients with single moderate coronary artery stenosis using three different non-invasive stress tests (exercise test, thallium scan and stress echocardiogram).4 Based on the findings of this study, the authors proposed a cut-off FFR value of 0.75 as a threshold for discrimination between ischaemia-inducible and ischaemia-noninducible lesions (see for example Figure 1). In the DEFER (Deferral versus Performance of Percutaneous Transluminal Coronary Angioplasty in Patients Without Documented Ischaemia) trial, the predictive value of this novel invasive index was tested for the first time in patients.5 The DEFER study was designed to investigate the safety and outcomes of deferring stenting in angiographic (FFR >0.75) stenoses. A total of 325 patients who were referred for percutaneous coronary intervention (PCI) due to an angiographic significant stenosis of >50 % were randomised to either the PCI group or PCI-deferral group. PCI was performed regardless of the FFR value in the PCI group. In the PCI-deferral group, PCI was undertaken only when the FFR was ≤0.75, and was deferred when the FFR was >0.75. At 12 months, event-free survival rates were similar in the deferral and PCI groups (89 versus 83 %, respectively; p=0.27). The results of this study indicate that a large number of patients referred for PCI on the basis of a coronary stenosis without objective proof of ischaemia had nonsignificant lesions as indicated by the FFR value. Stenting these patients did not reduce the rates of adverse cardiac events neither did it result in an improved functional class.5 Following on from the DEFER trial, the Fractional Flow Reserve Versus

116

Access at: www.ICRjournal.com

ICR_Heyndrickx_FINAL2.indd 116

Angiography for Multivessel Evaluation (FAME)6 and Fractional Flow Reserve-Guided Percutaneous Coronary Intervention Plus Optimal Medical Treatment Versus Optimal Medical Treatment Alone in Patients with Stable Coronary Artery Disease (FAME II)7 trials were designed to evaluate the superiority of FFR-guided revascularisation approaches compared with current medical practices in patients with stable coronary artery disease. In this review we analyse why and to what extent the results of the FAME trials should influence our current decision-making process in the catheterisation laboratory.

FAME I Trial The FAME trial compared two different revascularisation strategies in patients with stable coronary artery disease and multivessel disease (MVD): a standard angiographic-guided approach (revascularisation of lesions with >50 % stenosis) and an FFR-guided approach (revascularisation of lesions with an FFR ≤0.80).6 At 1 year follow-up, the primary endpoint (a composite of death, MI and repeat revascularisation) was significantly reduced in the FFR-guided group compared with the angiographic-guided group (13.2 versus 18.3 %; p=0.02). Regarding the secondary endpoints, while the reduction of all-cause mortality rates (1.8 versus 3.0 %; p=0.19), and reduction in MI rates (5.7 versus 8.7 %; p=0.07) were not significant, the reduction in the rates of the combined endpoints-a non prespecified secondary endpoint- (7.3 versus 11.1 %; p=0.04) was statistically significant. Collateral benefit of the FFR strategy was a decrease in the number of stents, a decrease in the amount of contrast and radiation time, resulting in a decrease in procedurerelated costs. In addition, the functional status of the patients was similar between groups, if not improved in the FFR group.6 These results were maintained up to 2 years after the index procedure.8 Subsequently, from 2 to 5 years, the risks for both groups developed

07/10/2016 00:55

The FAME Trials

similarly.9 Thus the FAME trial demonstrated, for the first time, the longterm safety and superiority of an FFR-guided approach, supporting the claim that functional rather than anatomical revascularisation should become the standard of care in this group of patients.

Figure 1: Coronary angiogram of right (R) and left (L) coronary artery (CA) together with FFR measurement of the L anterior descending artery (LAD) A

FAME II Trial The FAME II trial was designed to clarify whether PCI of only haemodynamic significant stenoses (i.e. lesions with FFR ≤0.80) combined with optimal medical therapy would be superior to optimal medical therapy alone as a first approach in patients with stable symptoms.7 Interestingly, recruitment in this trial was halted prematurely at the recommendation of the Data and Safety Monitoring Board after enrolment of 1220 patients due to observation of a highly significant difference in the incidence rates of the primary endpoint (cumulative incidence of death, MI or urgent revascularisation) between the PCI group and the medical-therapy group. The primary endpoint event rate at 1 year showed superiority of stenting with drug-eluting stents (DES) combined with optimal medical therapy over optimal medical therapy alone (4.3 versus 12.7 %; p<0.001), with a significant decrease in the incidence of urgent revascularisation (1.6 versus 11.1 %; p<0.001). However, the rate of death or MI did not differ between strategies.7 The premature stopping of recruitment may have influenced these latter data. The overall conclusion was that lesions with a positive FFR of ≤0.80 need to be revascularised upfront rather than started on optimal medical therapy.

FAMOUS-NSTEMI trial As in the FAME trial, in the FAMOUS-NSTEMI trial, two decision strategies were compared here, in patients with non ST-elevation acute coronary syndromes referred for urgent invasive management either within 72 hours of the acute ischaemic event or with recurrent ischaemia within 5 days after the index ischaemic event.10 Patients were randomised after the initial treatment decision based solely on angiography was made. FFR measurements were performed in all patients but only disclosed in the FFR-guided group. The results showed that when FFR data were disclosed the initial treatment option was changed in 21.6 % of patients thereby reducing the revascularisation rate. Overall, health outcome and quality of life in both randomised groups were similar despite the finding that in the FFR-guided group the rate of procedure-related MI was lower, but the rate of spontaneous major adverse cardiac events was higher during the 12-month follow-up period.10 These observations will need to be confirmed but appear to support the results from the FAME trials, stressing the point that treatment of ischaemia-inducible lesions should be an important aim in this population of patients.

The Grey Zone: FFR Index of 0.75–0.80 As mentioned earlier, the seminal FFR validation study demonstrated in patients with a discrete coronary stenosis an FFR threshold value of 0.75, below which ischaemia was inducible as demonstrated in at least one of three different non-invasive stress tests.4 The authors reported a sensitivity of FFR to detect reversible ischaemia of 88 %, with a specificity of 100 %. Although this may appear to be a robust figure, it is not infallible. There are important reasons for the predictive value being <100 %. 1. Maximal vasodilatation of the epicardial conduit vessels is a prerequisite for FFR measurements according to the proponents to avoid potential vasospasm during manipulation of the pressure wire.11 Vasoconstriction of the epicardial conduit vessels is known

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Heyndrickx_FINAL2.indd 117

(A) A diagnostic coronary angiogram in a 67-year-old man with typical exercise induced angina depicts two critical lesions on the RCA and L circumflex CA (LCx) with minor disease on the mid LAD. Stenting RCA and LCx with drug eluting stents (DES) did not result in alleviating all symptoms. A subsequent control angiogram revealed two patent stents on RCA and LCx and unchanged mild disease on the mid LAD. (B) FFR was then measured which revealed a hemodynamic significant lesion (FFR=0.67) requiring stenting of the mid LAD as well. This example is a point in case disclosing the limitations and stressing the inaccuracy of angiography for assessing functional lesion severity.

to occur in cases of increased orthosympathetic drive, yet with no untoward effects on coronary flow as long as the coronary vessels are normal. In the presence of underlying atherosclerosis, the occurrence of vasoconstriction may further reduce the vessel diameter on top of an already fixed obstruction.12 An FFR value of 0.75 during catheterisation with all vasomotion abolished by intracoronary nitrates may drop towards a value of 0.72 during exercise in cold weather due to some degree of superimposed alpha-mediated coronary vasoconstriction. Abolishing the vasomotion of epicardial conduit vessels before FFR measurements are taken may therefore sometimes mask the real FFR value occurring during daily activities. 2. The accuracy and reproducibility of the FFR measurement are based on maximum vasodilation following adenosine administration, which may not always be the case for a number of technical reasons such as the maximal used doses and the route of administration.13-15 3. Basic FFR metrics require simultaneous measurements of coronary venous or right atrial pressures, so as to integrate both maximum coronary flow and maximum collateral blood flow to

117

07/10/2016 00:55

Coronary the subtended myocardium (FFRmyo = [Pd–Pv]/[Pa–Pv]). Because generally, central venous pressure is close to zero, the simplified equation FFR = Pd/Pa has been advocated, which facilitates even more the routine use of this index.11 However, in the following theoretical example with a hypothetical set of pressures during maximum coronary vasodilation (Pd: 75 mmHg; Pa: 100 mmHg; Pv: 0) the calculated FFR value of 0.75 will decrease to 0.71 if Pv = 15 mmHg. Therefore, omission of coronary venous pressure (Pv) measurements may result in overestimation of FFR index.16 In contrast, in a mathematical analysis with Pd and Pa values between 50 and 140 mmHg and Pv values of 0.5, 10 and 15 mmHg, only 2.87 % of the combinations tested would have resulted in inappropriate high estimate of FFR if Pv was not considered.17 A recent analysis of 1600 coronary stenoses revealed that the differences between FFR and FFRmyo was minimal even in patients with markedly increased Pv values.18 FFR values above the grey zone (i.e. >0.80) did not yield values below the grey zone (i.e. ≤0.75) confirming that the impact of venous pressure on FFR is negligible indeed. 4. Interpreting FFR values may be less straightforward under certain conditions such as in the presence of elevated left ventricular enddiastolic pressure19 in patients with left ventricular dysfunction or in the presence of unprotected left main stem lesions with large myocardial mass at risk distal to the index lesion. The investigators of the FAME trial therefore decided that altering the FFR cut- off value towards 0.80 would eliminate the uncertainty of some stenosis with an FFR between 0.75 and 0.80. Accordingly, all the clinical trials and large registries demonstrating clinical benefit of FFRguided revascularisation over angiographic-guided strategies have been based on the cut-off value of 0.80. In a recent survey, 16 % of lesions interrogated with FFR were considered to fall in the grey zone based on their FFR value.20 Altering the FFR cut-off value towards 0.80 would increase its sensitivity, but at the cost of its specificity. By adhering strictly to the cut-off value of 0.75, a small number of patients might be denied the benefit of stenting. Were all lesions between 0.75 and with 0.80 to be stented, a larger number of patients would be denied the benefit of deferring stenting, with some, albeit small risk of procedural complications, restenosis, stent thrombosis or late-stent thrombosis. Adjedj and co-workers reviewed a large dataset of 1459 patients with single-vessel disease and compared the long-term outcome of patients with an FFR value within the grey zone (0.75–0.80) who were treated either by revascularisation or medical therapy.20 Rates

Kaul S, Lilly DR, Gascho JA, et al. Prognostic utility of the exercise thallium-201 test in ambulatory patients with chest pain: comparison with cardiac catheterization. Circulation 1988;77 :745–58. PMID: 3258193. Beller GA, Zaret BL. Contributions of nuclear cardiology to diagnosis and prognosis of patients with coronary artery disease. Circulation 2000;101 :1465–78. PMID: 10736294. Hachamovitch R, Hayes SW, Friedman JD, et al. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003;107 :2900–7. DOI: 10.1161/01. CIR.0000072790.23090.41; PMID: 12771008. Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334 :1703–8. DOI: 10.1056/NEJM199606273342604; PMID: 8637515. Bech GJW, De Bruyne B, Pijls NH, et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis. Circulation 2001;103 :2928–34. PMID: 11413082. Tonino PAL, De Bruyne B, Pijls NH, et al. Fractional flow

118

ICR_Heyndrickx_FINAL2.indd 118

of major adverse cardiac events (death, MI and any revascularisation) up to 5 years were comparable between medical therapy and revascularisation groups (13.9 and 11.2%, respectively; p=0.30), whereas a trend towards a higher rate of death or MI was observed in the medical therapy group (9.4 versus 4.8 %, respectively; p=0.06).

Post-FAME Era The overwhelmingly convincing data from the FAME and the FAMOUSNSTEMI trials should not be ignored. The uniqueness of the FFR index as a marker of ischaemia-prone lesions in patients with coronary artery disease is well known. However, despite the widely publicised results from the FAME trials, the extensive workshops on use and interpretation of FFR and the recommendation for FFR use as a diagnostic tool according to current guidelines,21 the actual rate of FFR use in clinical practice remains disappointingly low (<7 % in the United States).22 Several reasons for this low-level FFR use have been cited; however, cost and reimbursement issues are likely the most valid limitations that discourage people from routine FFR use. Such hindrance of a more liberal use of the pressure wires during diagnostic coronary angiography may be resolved in the future with the further development of non-invasive methods that allow FFR calculations derived from coronary computed tomographic angiography23,24 or from 3D quantitative coronary angiography.25 Whether a cut-off value of 0.75 or 0.80 is used, there will be some risk of false-negative results. Where FFR values fall within the grey zone, treatment decisions should not be made based on a single index, but after having considered all of the clinical information available as well as the objective quantitative data, including risk assessment and patient preferences.

Conclusion The FAME trials have lifted the last road blocks towards the general acceptance by the cardiology community of this novel paradigm in which the diagnostic focus of coronary lesions is shifted from anatomical characteristics to a functional impact on myocardial perfusion. This unique vision on how to evaluate severity and prognosis of coronary lesions should force us to rethink our current algorithm for the treatment of patients with chest pain where FFR measurements may supplant non-invasive stress tests, which are only being performed in <50 % of patients prior to elective PCI.26 However, it will take some time to alter the current course of patient care. n

reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360 :213–24. DOI: 10.1056/NEJMoa0807611; PMID: 19144937. 7. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367 :991–1001. DOI: 10.1056/ NEJMoa1205361; PMID: 22924638. 8. Pijls NH, Fearon WF, Tonino PA, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2 year follow-up the FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) study. J Am Coll Cardiol 2010;56 :177–84. DOI: 10.1016/j.jacc.2010.04.012; PMID: 20537493. 9. van Nunen LX, Zimmermann FM, Tonino PA, et al. Fractional flow reserve versus angiography for guidance of PCI in patients with multivessel coronary artery disease (FAME): 5-year followup of a randomised controlled trial. Lancet 2015;386:1853–60. DOI: 10.1016/S0140-6736(15)00057-4; PMID: 26333474. 10. Layland J, Oldroyd KG, Curzen N, et al. Fractional Flow reserve vs. angiography in guiding management to optimize outcomes in non-ST-segment elevation myocardial infarction: the British Heart Foundation FAMOUS-NSTEMI randomized

trial. Eur Heart J 2015;36 :100–11. DOI: 10.1093/eurheartj/ ehu338; PMID: 25179764. 11. Pijls NH, De Bruyne B. Coronary Pressure. Second Edition. Kluwer Academic Publishers. Dordrecht / Boston / London. 2000. Chapter 5. Practical Set-up of coronary pressure measurements. pp.83–114. 12. Heusch G, Baumgart D, Camici P, et al. Alpha-adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation 2000;101 :689–94. PMID: 10673263. 13. Pijls NH, Tonino PA. The crux of maximum hyperemia: the last remaining barrier for routine use of fractional flow reserve. JACC Cardiovasc Interv 2011;4 :1093–5. DOI: 10.1016/j. jcin.2011.08.007; PMID: 22017934. 14. Nair PK, Marroquin OC, Mulukutla SR, et al. Clinical utility of regadenoson for assessing fractional flow reserve. JACC Cardiovasc Interv 2011;4 :1085–92. DOI: 10.1016/j. jcin.2011.07.011; PMID: 22017933. 15. De Luca G, Venegoni L, Iorio S, et al. Effects of increasing doses of intracoronary adenosine on the assessment of fractional flow reserve. JACC Cardiovasc Interv 2011;4 : 1079–84. DOI: 10.1016/j.jcin.2011.08.004; PMID: 22017932. 16. Layland J, Wilson AM, Whitbourn RJ, et al. Impact of right atrial pressure on decision-making using fractional flow

INTERVENTIONAL CARDIOLOGY REVIEW

07/10/2016 00:55

The FAME Trials

17.

18.

19.

20.

reserve (FFR) in elective percutaneous intervention. Int J Cardiol 2013;167 :951–3. DOI: 10.1016/j.ijcard.2012.03.087; PMID: 22475843. Kumar GT. Letter to the editor: The influence of right atrial pressure on fractional flow reserve. J Invasive Cardiol 2012;24 :A43–4. PMID: 23043042. Toth GG, De Bruyne B, Rusinaru D, et al. Impact of right atrial pressure on fractional flow reserve measurements. Comparison of fractional flow reserve and myocardial flow reserve in 1,600 coronary stenoses. JACC Cardiovasc Interv 2016;9 :453–9. DOI: 10.1016/j.jcin.2015.11.021; PMID: 26896888. Leonardi RA, Townsend JC, Patel CA, et al. Left ventricular end-diastolic pressure affects measurements of fractional flow reserve. Cardiovasc Revasc Med 2013;14 :218–22. DOI: 10.1016/j.carrev.2013.06.001; PMID: 23886870. Adjedj J, De Bruyne B, Floré V, et al. Significance of intermediate values of fractional flow reserve in patients

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Heyndrickx_FINAL2.indd 119

with coronary artery disease. Circulation 2016;133 :502–8. DOI: 10.1161/CIRCULATIONAHA.115.018747; PMID: 26733607. 21. Windecker S, Kolh PH, Alfonso T, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization. The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35: 2541–619. DOI: 10.1093/eurheartj/ehu278; PMID: 25173339. 22. Riley RF, Don CW, Powell W, et al. Trends in coronary revascularization in the United States from 2001 to 2009: recent declines in percutaneous coronary intervention volumes. Circ Cardiovasc Qual Outcomes 2011;4 :193–7. DOI: 10.1161/CIRCOUTCOMES.110.958744; PMID: 21304092. 23. Wong DTL, Ko BS, Cameron JD, et al. Transluminal attenuation gradient in coronary computed tomography angiography is a novel noninvasive approach to the

identification of functionally significant coronary artery stenosis: a comparison with fractional flow reserve. J Am Coll Cardiol 2013;61 :1271–9. DOI: 10.1016/j.jacc.2012.12.029; PMID: 23414792. 24. Nørgaard BL, Leipsic J, Koo BK, et al. Coronary computed tomography angiography derived fractional flow reserve and plaque stress. Curr Cardiovasc Imaging Rep 2016;9 :2. DOI: 10.1007/s12410-015-9366-5; PMID: 26941886. 25. Tu S, Barbato E, Köszegi Z, et al. Fractional flow reserve calculation from 3-dimensional quantitative coronary angiography and TIMI frame count: a fast computer model to quantify the functional significance of moderately obstructed coronary arteries. JACC Cardiovasc Interv 2014;7 :768–77. DOI: 10.1016/j.jcin.2014.03.004; PMID: 25060020. 26. Lin GA, Dudley RA, Lucas FL, et al. Frequency of stress testing to document ischemia prior to elective percutaneous coronary intervention. JAMA 2008;300 :1765–73. DOI: 10.1001/ jama.300.15.1765; PMID: 18854538.

119

07/10/2016 00:55

Coronary

Emerging Technology Update Intravascular Photoacoustic Imaging of Vulnerable Atherosclerotic Plaque Min W u, 1 Antonius FW v a n d e r S t e e n , 1 ,2 ,3 ,4 E v e l y n Re g a r 5 a n d G i j s v a n S o e s t 1 1. Department of Biomedical Engineering, Thorax Centre, Erasmus Medical Center, Rotterdam, The Netherlands; 2. Interuniversity Cardiology Institute of The Netherlands, Netherlands Heart Institute, Utrecht, The Netherlands; 3. Department of Imaging Science and Technology, Delft University of Technology, Delft, The Netherlands; 4. Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; 5. Department of interventional cardiology, Thorax Center, Erasmus Medical Center, Rotterdam, The Netherlands

Abstract The identification of vulnerable atherosclerotic plaques in the coronary arteries is emerging as an important tool for guiding atherosclerosis diagnosis and interventions. Assessment of plaque vulnerability requires knowledge of both the structure and composition of the plaque. Intravascular photoacoustic (IVPA) imaging is able to show the morphology and composition of atherosclerotic plaque. With imminent improvements in IVPA imaging, it is becoming possible to assess human coronary artery disease in vivo. Although some challenges remain, IVPA imaging is on its way to being a powerful tool for visualising coronary atherosclerotic features that have been specifically associated with plaque vulnerability and clinical syndromes, and thus such imaging might become valuable for clinical risk assessment in the catheterisation laboratory.

Keywords Vulnerable plaque, intravascular photoacoustic imaging, atherosclerosis, intravascular imaging, coronary artery disease Disclosure: The authors have no conflicts of interest to declare. Submitted: 18 April 2016 Accepted: 8 September 2016 Citation: Interventional Cardiology Review 2016;11(2):120–3 DOI: 10.15420/icr.2016:13:3 Correspondence: Gijs van Soest, Department of Biomedical Engineering, Thorax Center, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands. E: g.vansoest@erasmusmc.nl

Vulnerable atherosclerotic plaque comprises a lipid-rich necrotic core, covered by a thin fibrous cap, that is weakened by macrophage infiltration.1 Plaques that have this morphology and composition have a greater probability of being associated with acute coronary syndromes in clinical studies.2,3 Coronary artery disease is most commonly triggered by the rupture of vulnerable plaque and thrombosis.4 The identification of vulnerable plaque is emerging as an important element in coronary artery disease diagnosis and treatment. In the past three decades, several imaging modalities have been employed to identify vulnerable plaque. Coronary angiography is the oldest of these modalities and can only visualise the artery lumen, not the artery wall and atherosclerotic lesions. Moreover, angiography creates images of a three-dimensional moving object that are presented in a two-dimensional plane. Intravascular, catheter-based imaging methods can be safely used in a routine catheterisation laboratory population5 and offer direct visualisation of the artery wall. Intravascular ultrasound (IVUS) imaging has been used in routine clinical practice for more than 20 years. Due to the limited acoustic contrast between soft tissues, the conventional grayscale IVUS image is not sensitive enough to differentiate plaque composition, except for the presence of calcium.6,7 While the application of an advanced analysis algorithm to IVUS images – virtual histology IVUS – has improved plaque composition characterisation,8 no data yet support its accuracy in the detection of lipid-rich necrotic plaque core.9–11 IVUS palpography is a technology used to assess local mechanical

120

Access at: www.ICRjournal.com

ICR_van Soest_FINAL2.indd 120

plaque properties based on tissue deformation caused by intraluminal pressure.12 It can only sense the stiffness of the tissue, however, and cannot directly image the tissue, and it only assesses the first 450 μm of the arterial wall.12 Light-based intravascular optical coherence tomography (IVOCT) creates high-resolution images (approximately 15 μm) with backscattered light from the tissue13 and can image plaque components such as calcium, lipid and thrombus. IVOCT currently relies on qualitative image interpretation to distinguish these features.14,15 The depth to which IVOCT penetrates is only 1–2 mm into the atherosclerotic tissue, which means it often cannot see the extent of the plaque up to the adventitia. Near-infrared spectroscopy (NIRS) is another light-based imaging modality for the detection of lipid-rich necrotic core in plaque.16 It provides a probability for the presence of coronary lipid based on the spectral analysis of backscattered light;17 however, NIRS cannot identify the amount and location of lipids, which may be important in risk assessment.18 Several other innovative optical modalities have been proposed recently19–22 that are currently being evaluated in clinical trials. The ability of these technologies to provide reliable, spatially-precise, quantitative imaging of plaque lipid content is yet to be determined. In this paper, a newer modality is reviewed: intravascular photoacoustic (IVPA) imaging. This is an optical–acoustic hybrid imaging modality. IVPA is currently being developed to show both the morphology and chemical composition of the artery wall with a good imaging depth and resolution. This technology takes advantage of the unique

07/10/2016 01:18

IVPA Imaging of Vulnerable Atherosclerotic Plaque

optical absorption contrast between different tissues and reasonably large penetration depth owing to the low acoustic attenuation in soft tissues.23,24 Published experimental data suggest it may be a strong contender for detailed plaque characterisation and the identification of plaque at increased risk of causing clinical sequelae.

Figure 1: Illustration of the Intravascular Photoacoustic Imaging Principle

coronary artery catheter 0

The Principles of IVPA Imaging of Atherosclerotic Plaque IVPA imaging requires short laser pulses, lasting a few nanoseconds, to be applied to irradiate the artery wall. Absorption of the light converts the optical energy into heat in the tissue and causes thermoelastic expansion, leading to a transient pressure rise (the laser pulse duration is shorter than both the stress relaxation and the thermal diffusion times). Figure 1 illustrates the principles involved in IVPA imaging. The specific optical absorption spectra of lipids and other pure substances can be related to the identification of plaque.25 Various biomarkers present in plaques have been explored for their usefulness in IVPA imaging, with lipid being the most frequently used. IVPA imaging of plaque lipids can be performed at around 1.2 μm or 1.72 μm due to the high lipid-specific absorption contrast with relatively high resolution (~50 μm) and reasonable penetration depth.26 At 1.2 μm the laser’s maximal permissible exposure limit is 20 mJ/cm2 and at 1.72 μm it is 1 J/cm2, according to the American National Standards Institute laser safety standard.27,28 NIRS also makes use of lipid to identify potentially vulnerable plaque, but there is no depth resolution. The capability of IVPA to produce images of atherosclerotic plaque lipids has been demonstrated extensively with ex vivo tissues and in vivo animal models.26,27,29–33 Macrophages are an important cell type related to the progression of atherosclerosis34 and the specific imaging of plaque macrophage content is a potentially interesting feature when identifying vulnerable plaque.36 Macrophages do not exhibit a strong intrinsic contrast in the way lipids do, therefore exogenous imaging contrast agents with high optical absorption are applied in order to visualise them using IVPA imaging.36,37 Furthermore, given that the activity of the enzyme matrix metalloproteinase (MMP) is an indicator of plaque instability, the localisation of MMP activity with an MMP-sensitive activatable probe in vulnerable plaques in human carotid specimens has been achieved using photoacoustic imaging.38 More recently, an ApoE-/- mouse in vivo model injected with a photoacoustic ICG@PEG-Ag2S nanoprobe was successful in imaging plaque.39

Developing IVPA Imaging for Clinical Use Encouraged by the capability of IVPA to create images of vulnerable atherosclerotic plaque, an intensive research effort is on-going to incorporate IVPA imaging into clinical applications.

Miniaturising the IVPA Catheter A miniature, and highly sensitive, catheter for IVPA imaging is an essential element if IVPA imaging technology is to enter common use. As IVPA is an intrinsically multimodal imaging technique, the catheter’s technical requirements are harder to meet than for single-modality probes like optical coherence tomography or IVUS catheters. A typical IVPA imaging catheter consists of an optical part for light delivery and a broadband ultrasound transducer. The optical part is usually a combination of an optical fibre and a mirror or a single-angle polished optical fibre.40 Two IVPA catheter designs are shown in Figure 2. The unit shown in Figure 2A provides the

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_van Soest_FINAL2.indd 121

Laser irradiation

Light absorption and thermoelastic expansion. (The green target has a higher optical absorption than red one for the incident light)

Ultrasound signal generation (black arcs)

time

Intravascular photoacoustic signal received: the photoacoustic amplitude from the green target is higher than red due to the higher optical absorption

Figure 2: Different Intravascular Photoacoustic (IVPA) Catheter Designs A

(A) A collinear IVPA catheter. (B) An IVPA catheter with a longitudinal offset between optical and acoustic beams, where red is the optical beam and green the ultrasound beam [adapted from Wu et al., 201041].

greatest reported sensitivity. Miniaturisation is challenging, however, and this unit is currently too large for intravascular application, having a diameter of 2.9 mm.27,28 Another design possibility – one that is favoured for miniaturisation – incorporates an offset between the optical fibre and ultrasound transducer, either longitudinally41,42 (see Figure 2B) or laterally.43 The smallest IVPA catheter reported to date that uses this design has an outer diameter of 0.9 mm, which is below the threshold of 1 mm desired for clinical translation into coronary arteries.44

Efficient and Specific Plaque Identification Lipids are found in the plaque inside the artery wall, which is rich in cholesterol and cholesteryl esters,45,46 as well as in peri-adventitial fat tissue around the artery, which contains a mixture of fatty acids.47 The spectral contrast between plaque lipids and peri-adventitial fat makes it possible to differentiate between them using spectroscopic IVPA imaging (sIVPA).26 As a consequence of this, the presence and location of lipids within a plaque can be reliably and rapidly displayed during catheter pullback, using both cross-sectional and longitudinal data display. Performing multiple wavelength sIVPA imaging, however, has an impact on the complexity, cost andspeed of the imaging system. Minimisation of the number of wavelengths for the differentiation of different lipids or improving the efficiency for specific lipid differentiation is necessary for practical application. The possibility of specific plaque lipid imaging using sIVPA with limited number of wavelengths has been investigated (see Figure 3).26,48 It is possible to achieve about 70 % true positive and 15 % false positive pixel identification of plaque lipids based on the relative difference between amplitudes of only two wavelengths (see Figure 4).49

High-speed IVPA Imaging of Atherosclerotic Plaque Despite successful plaque identification by IVPA imaging, the low imaging speed limits its application in practice. Lipid specificity remains limited by the single-wavelength operation and the average optical power remains quite high (up to 1 W), which raises concerns about

121

07/10/2016 01:18

Coronary Figure 3: Lipid Identification in an Atherosclerotic Human Coronary Artery

(A) Plaque lipid identification based on a three-wavelength correlation with the reference spectra of cholesterol in the 1.2 mm spectral range. (B) Peri-adventitial fat identification based on three-wavelength correlation with the reference spectra of human peri-adventitial fat tissue. (C) Histology result following Oil Red O staining. All lipid identifications have been laid over registered intravascular ultrasound images. Adapted from Jansen et al., 2013.48

thermal damage to the patient’s artery and the potential hazard to the operator resulting from skin and eye exposure. With the introduction of higher pulse-rate laser systems (2 kHz), IVPA imaging speed has been increased from about 0.3 to 1 frame per second.27,28,50 This represents a significant step forward, but is still not practical. More and faster IVPA imaging systems are, however, on the horizon. A fast multiplewavelength sIVPA imaging system with potentially ~5 frames per second has been developed that is capable of imaging at a low-energy pulse.44

Discussion IVPA imaging shows great promise in detecting the morphology and composition (e.g. lipid deposition) of arterial lipid plaque burden. Owing to the extensive research on IVPA imaging, several important milestones have been passed, with the development of a miniature flexible catheter (<1 mm in diameter), high-efficiency specific imaging of vulnerable plaque composition and the development of a highspeed IVPA imaging system (~ 5 frames per second). Some challenges remain, however, in the further development of IVPA imaging. Most current IVPA imaging systems require the artery to be cleared of blood by flushing for a better photoacoustic signal-to-noise ratio. It is in principle possible to perform IVPA imaging at 1.72 μm without flushing, due to the similarity in the optical absorption property of blood and water-based tissues. Wang et al. performed the first in vivo IVPA imaging (at 1,720 nm) in a hypercholesterolemic rabbit model through blood.29 Further IVPA imaging through blood – and in and ex vivo human tests – must await the resolution of other clinical implementation issues described in this article. Although the imaging speed has been significantly improved,51–53 it is still not fast

Schaar JA, Muller JE, Falk E, et al. Terminology for highrisk and vulnerable coronary artery plaques. Eur Heart J 2004;25 :1077–82. PMID: 15191780 Kini AS, Motoyama S, Vengrenyuk Y, et al. Multimodality intravascular imaging to predict periprocedural myocardial infarction during percutaneous coronary intervention. JACC Cardiovasc Interv 2015;8 :937–45. DOI: 10.1016/ j.jcin.2015.03.016; PMID: 26088511 Goldstein JA, Maini B, Dixon SR, et al. Detection of lipidcore plaques by intracoronary near-infrared spectroscopy identifies high risk of periprocedural myocardial infarction. Circ Cardiovasc Interv 2011;4 :429–37. DOI: 10.1161/ CIRCINTERVENTIONS.111.963264; PMID: 219723991. World Health Organization. Cardiovascular diseases (CVDs). January 2015. Available at: http://www.who.int/topics/ cardiovascular_diseases/en/ (accessed 9 September 2016) van der Sijde JN, Karanasos A, van Ditzhuijzen NS, et al. Safety of optical coherence tomography in daily practice: a comparison with intravascular ultrasound. Eur Heart J Cardiovasc Imag 2016:jew037. DOI: http://dx.doi.org/10.1093/ ehjci/jew037 Allen TJ, Hall A, Dhillon AP, et al. Spectroscopic photoacoustic imaging of lipid-rich plaques in the human

122

ICR_van Soest_FINAL2.indd 122

Figure 4: Ex Vivo Lipid Differentiation Result of the Atherosclerotic Left Anterior Ascending Coronary Artery of an 80-year-old Man

(A) Histology: Oil Red O (ORO) staining of the intravascular photoacoustic/intravascular ultrasound image in cross-section. The lipids are shown in red. (B) Lipid differentiation map overlaid on the co-registered intravascular ultrasound image of the coronary artery. The lipids in the plaques are yellow and lipids in the peri-adventitial tissue are red. The green contour indicates the external elastic lamina. Adapted from Wu et al., 2015.49

enough for clinical use. Recently, it was found that the sensitivity of IVPA catheters can be increased by an order of magnitude by matching the frequency response of the receiving transducer to the low-frequency range.54,55 This enables imaging with lower pulse energy, allowing for fast laser sources with moderate output power. Other challenges in adapting IVPA imaging to the clinical setting include the cost and robustness of the laser system and the choice of catheter sheath material, which needs to be transparent for ultrasound and infrared light. These topics being investigated in on-going engineering research.

Conclusion IVPA imaging is unique in its biochemical specificity and can offer the clinician direct, validated visualisation of coronary plaque lipid. To many clinicians, the ideal tool for guiding atherosclerotic plaque diagnosis and interventions requires high resolution to characterise the thin cap, high sensitivity to detect lipids for plaque visualisation in the artery, and a reasonable depth of penetration for plaque burden assessment. To achieve this, the combination of IVOCT and IVPA appears to be a promising choice, but at the cost of integrating an extra optical coherence tomography laser system. However, the natural progression of plaque with vulnerable characteristics is complex and the development and application of clinical tools for its assessment is, likewise, challenging. To date, IVPA imaging remains a research tool; future advances in technology will determine to what degree it will be of use in clinical practice. n

aorta in the 740 to 1400 nm wavelength range. J Biomed Opt 2012;17 :061209–10. DOI: 10.1117/1.JBO.17.6.061209; PMID: 22734739 7. Choudhury RP, Fuster V, Fayad ZA. Molecular, cellular and functional imaging of atherothrombosis. Nat Rev Drug Discov 2004;3 :913–25. PMID: 15520814 8. Nair A, Kuban BD, Tuzcu EM, et al. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation 2002;106 :2200–6. PMID: 12390948 9. Thim T, Hagensen MK, Wallace-Bradley D, et al. Unreliable assessment of necrotic core by virtual histology intravascular ultrasound in porcine coronary artery disease. Circ Cardiovasc Imaging 2010;3 :384–91. DOI: 10.1161/ CIRCIMAGING.109.919357; PMID: 20460496 10. Shin ES, Garcia-Garcia HM, Ligthart JM, et al. In vivo findings of tissue characteristics using iMap IVUS and virtual histology IVUS. EuroIntervention 2011;6 :1017–9. DOI: 10.4244/ EIJV6I8A175; PMID: 21330252 11. Puri R, Worthley MI, Nicholls SJ. Intravascular imaging of vulnerable coronary plaque: current and future concepts. Nat Rev Cardiol 2011;8 :131–9. DOI: 10.1038/nrcardio.2010.210; PMID: 21263456

12. Schaar JA, van der Steen AF, Mastik F, et al. Intravascular palpography for vulnerable plaque assessment. J Am Coll Cardiol 2006;47 :C86–91. PMID: 16631515 13. Tearney GJ, Regar E, Akasaka T, et al; International Working Group for Intravascular Optical Coherence Tomography (IWG-IVOCT). Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation. J Am Coll Cardiol 2012;59:1058–72. DOI: 10.1016/j.jacc.2011.09.079; PMID: 22421299 14. Jansen K, van Soest G, van der Steen AFW. Intravascular photoacoustic imaging: A new tool for vulnerable plaque identification. Ultrasound Med Biol 2014;40 :1037–48. DOI: 10.1016/j.ultrasmedbio.2014.01.008; PMID: 24631379 15. van Soest G, Goderie T, Regar E, et al. Atherosclerotic tissue characterization in vivo by optical coherence tomography attenuation imaging. J Biomed Opt 2010;15 :011105. DOI: 10.1117/1.3280271; PMID: 20210431 16. Gardner CM, Tan H, Hull EL, et al. Detection of lipid core coronary plaques in autopsy specimens with a novel catheter-based near-infrared spectroscopy system. JACC Cardiovasc Imaging 2008;1 :638–48. DOI: 10.1016/j.

INTERVENTIONAL CARDIOLOGY REVIEW

07/10/2016 01:18

IVPA Imaging of Vulnerable Atherosclerotic Plaque

jcmg.2008.06.001; PMID: 19356494 17. Waxman S, Dixon SR, L’Allier P, et al. In vivo validation of a catheter-based near-infrared spectroscopy system for detection of lipid core coronary plaques: initial results of the SPECTACL study. J Am Coll Cardiol Img 2009;2 :858–68. DOI: 10.1016/j.jcmg.2009.05.001; PMID: 19608137 18. Niccoli G, Liuzzo G, Montone RA, et al. Advances in mechanisms, imaging and management of the unstable plaque. Atherosclerosis 2014;233 :467–77. DOI: 10.1016/ j.atherosclerosis.2014.01.036; PMID: 24530781 19. Vinegoni C, Botnaru I, Aikawa E, et al. Indocyanine green enables near-infrared fluorescence imaging of lipid-rich, inflamed atherosclerotic plaques. Sci Transl Med 2011;3 : 84ra45. DOI: 10.1126/scitranslmed.3001577; PMID: 21613624 20. Ughi GJ, Wang H, Gerbaud E, et al. Clinical characterization of coronary atherosclerosis with dual-modality OCT and nearinfrared autofluorescence imaging. JACC Cardiovasc Imaging 2016; DOI: 10.1016/j.jcmg.2015.11.020; PMID: 26971006 PMCID: epub ahead of press 21. Nadkarni SK, Bouma BE, Helg T, et al. Characterization of atherosclerotic plaques by laser speckle imaging. Circulation 2005;112 :885–92. DOI: 10.1161/ CIRCULATIONAHA.104.520098; PMID: 16061738 22. van Soest G, van der Steen AFW, Regar E. Autofluorescence: a new NIR on the block. JACC Cardiovasc Imaging 2016; DOI:10.1016/j.jcmg.2015.12.011; PMID: 26971002: epub ahead of press 23. Jansen K, van Soest G, van der Steen T. Photoacoustic imaging of coronary arteries: current status and potential clinical application. In: Arampatzis C, McFadden EP, Michalis LK, Virmani R, Serruys PW (eds). Coronary Atherosclerosis: Current Management and Treatment. First edn. London: Informa Healthcare, 2012;166–74. 24. Schoenhagen P, Vince DG. Intravascular photoacoustic tomography of coronary atherosclerosis riding the waves of light and sound. J Am Coll Cardiol 2014;64 :391–3. DOI: 10.1016/j.jacc.2014.05.018; PMID: 25060375 25. Fleming CP, Eckert J, Halpern EF, et al. Depth resolved detection of lipid using spectroscopic optical coherence tomography. Biomed Opt Express 2013;4 :1269–84. DOI: 10.1364/BOE.4.001269; PMID: 24009991 26. Jansen K, Wu M, van der Steen AF, et al. Photoacoustic imaging of human coronary atherosclerosis in two spectral bands. Photoacoustics 2014;2:12–20. DOI: 10.1016/j.pacs.2013.11.003 27. Wang P, Ma T, Slipchenko MN, et al. High-speed Intravascular photoacoustic imaging of lipid-laden atherosclerotic plaque enabled by a 2-kHz barium nitrite raman laser. Sci Rep 2014;4 :6889. DOI: 10.1038/srep06889; PMID: 25366991 28. Hui J, Yu Q, Ma T, et al. High-speed intravascular photoacoustic imaging at 1.7 μm with a KTP-based OPO. Biomed Opt Express 2015;6 :4557–66. DOI: 10.1364/ BOE.6.004557; PMID: 26601018 29. Wang B, Karpiouk A, Yeager D, et al. Intravascular photoacoustic imaging of lipid in atherosclerotic plaques in

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_van Soest_FINAL2.indd 123

the presence of luminal blood. Opt Lett 2012;37 :1244–6. DOI: 10.1364/OL.37.001244; PMID: 22466209 30. Allen TJ, Hall A, Dhillon A, et al. (eds). Photoacoustic imaging of lipid rich plaques in human aorta. In: Oraevsky AA, Wang LV (eds) Photons Plus Ultrasound: Imaging and Sensing 2010 . San Francisco, California: SPIE, 2010. DOI: 10.1117/12.842205 31. Jansen K, van der Steen AFW, van Beusekom HMM, et al. Intravascular photoacoustic imaging of human coronary atherosclerosis. Opt Lett 2011;36 :597–9. DOI: 10.1364/ OL.36.000597; PMID: 21368919 32. Wang B, Su JL, Amirian J, et al. Detection of lipid in atherosclerotic vessels using ultrasound-guided spectroscopic intravascular photoacoustic imaging. Opt Express 2010;18 :4889–97. DOI: 10.1364/OE.18.004889; PMID: 20389501 33. Wang P, Wang HW, Sturek M, et al. Bond-selective imaging of deep tissue through the optical window between 1600 and 1850 nm. J Biophotonics 2012;5 :25–32. DOI: 10.1002/ jbio.201100102; PMID: 22125288 34. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685–95. PMID: 15843671 35. Tearney GJ, Yabushita H, Houser SL, et al. Quantification of macrophage content in atherosclerotic plaques by optical coherence tomography. Circulation 2003;107 :113–9. PMID: 12515752 36. Wang B, Joshi P, Sapozhnikova V, et al. (eds). Intravascular photoacoustic imaging of macrophages using molecularly targeted gold nanoparticles. Proc. SPIE 7564, Photons Plus Ultrasound: Imaging and Sensing 2010 2010:75640A. DOI: 10.1117/12.841070 37. Wang B, Yantsen E, Larson T, et al. Plasmonic intravascular photoacoustic imaging for detection of macrophages in atherosclerotic plaques. Nano Lett 2009;9 :2212–7. DOI: 10.1021/nl801852e; PMID: 18844426 38. Razansky D, Harlaar NJ, Hillebrands JL, et al. Multispectral optoacoustic tomography of matrix metalloproteinase activity in vulnerable human carotid plaques. Mol Imaging Biol 2012;14 :277–85. DOI: 10.1007/s11307-011-0502-6. 39. Wu C, Zhang Y, Li Z, et al. A novel photoacoustic nanoprobe of ICG@ PEG-Ag 2 S for atherosclerosis targeting and imaging in vivo. Nanoscale 2016;8 :12531-9. DOI: 10.1039/c6nr00060f; PMID: 26853187 40. Karpiouk AB, Wang B, Emelianov SY. Development of a catheter for combined intravascular ultrasound and photoacoustic imaging. Rev Sci Instrum 2010;81 :014901. DOI: 10.1063/1.3274197; PMID: 20113121 41. Wu M, Jansen K, Springeling G, et al. Impact of device geometry on the imaging characteristics of an intravascular photoacoustic catheter. Appl Opt 2014;53 :8131–9. DOI: 10.1364/AO.53.008131; PMID: 25607973 42. Jansen K, Springeling G, Lancee C, et al. An intravascular photoacoustic imaging catheter. Presented at: IEEE

International Ultrasonics Symposium, San Diego, 11–14 October 2010. 43. Li X, Wei W, Zhou Q, et al. Intravascular photoacoustic imaging at 35 and 80 MHz. J Biomed Opt 2012;17 :106005-1. DOI: 10.1117/1.JBO.17.10.106005; PMID: 23224004 44. Li Y, Gong X, Liu C, et al. High-speed intravascular spectroscopic photoacoustic imaging at 1000 A-lines per second with a 0.9-mm diameter catheter. J Biomed Opt 2015;20 :065006. DOI: 10.1117/1.JBO.20.6.065006; PMID: 26098356 45. Lundberg B. Chemical composition and physical state of lipid deposits in atherosclerosis. Atherosclerosis 1985;56 :93–110. PMID: 4026939 46. Stegemann C, Drozdov I, Shalhoub J, et al. Comparative lipidomics profiling of human atherosclerotic plaques. Circ Cardiovasc Genet 2011;4 :232–42. DOI: 10.1161/ CIRCGENETICS.110.959098; PMID: 21511877 47. Tsai CL, Chen JC, Wang WJ. Near-infrared absorption property of biological soft tissue constituents. J Med Biol Eng 2001;21 :7–14. 48. Jansen K, Wu M, van der Steen AF, et al. Lipid detection in atherosclerotic human coronaries by spectroscopic intravascular photoacoustic imaging. Opt Express 2013;21 :21472–84. DOI: 10.1364/OE.21.021472; PMID: 24104022 49. Wu M, Jansen K, van der Steen AF, et al. Specific imaging of atherosclerotic plaque lipids with two-wavelength intravascular photoacoustics. Biomed Opt Express 2015;6 : 3276–86. DOI: 10.1364/BOE.6.003276; PMID: 26417500 50. Piao Z, Ma T, Li J, et al. High speed intravascular photoacoustic imaging with fast optical parametric oscillator laser at 1.7 μm. Appl Phys Lett 2015;107 :083701. PMID: 26339072 51. Sethuraman S, Aglyamov SR, Amirian JH, et al. Intravascular photoacoustic imaging using an IVUS imaging catheter. IEEE Trans Ultrason Ferroelectr Freq Control 2007;54 (5):978–86. PMID: 17523562 52. Sethuraman S, Amirian JH, Litovsky SH, et al. Ex vivo characterization of atherosclerosis using intravascular photoacoustic imaging. Opt Express 2007;15 :16657–66. PMID: 19550952 53. Sethuraman S, Amirian JH, Litovsky SH, et al. Spectroscopic intravascular photoacoustic imaging to differentiate atherosclerotic plaques. Opt Express 2008;16 :3362–7. PMID: 18542427 54. Daeichin V, Wu M, de Jong N, et al. Frequency analysis of the photoacoustic signal generated by coronary atherosclerotic plaque. Ultrasound Med Biol 2016;42 :2017–25. DOI: 10.1016/ j.ultrasmedbio.2016.03.015; PMID: 27181689 55. Daeichin V, Chen C, Ding Q, et al. A broadband polyvinylidene difluoride-based hydrophone with integrated readout circuit for intravascular photoacoustic imaging. Ultrasound Med Biol 2016;42 :1239–43. DOI: 10.1016/ j.ultrasmedbio.2015.12.016; PMID: 26856788

123

07/10/2016 01:18

Coronary

The Need For Dedicated Bifurcation Stents: A Critical Analysis Maciej Lesiak Poznan University of Medical Sciences, Poznan, Poland

Abstract There is growing evidence that optimally performed two-stent techniques may provide similar or better results compared with the simple techniques for bifurcation lesions, with an observed trend towards improvements in clinical and/or angiographic outcomes with a twostent strategy. Yet, provisional stenting remains the treatment of choice. Here, the author discusses the evidence – and controversies – concerning when and how to use complex techniques.

Keywords two-stent technique, dedicated bifurcation stent, stent Disclosure: The author has no conflicts of interest to disclose. Received: 11 July 2016 Accepted: 9 September 2016 Citation: Interventional Cardiology Review 2016;11(2):124–7 DOI: 10.15420/icr.2016:22:2 Correspondence: Maciej Lesiak, Department of Cardiology, Poznan University of Medical Sciences, 41 Jackowskiego Street, 60-512, Poznan, Poland. E: maciej.lesiak@skpp.edu.pl

While provisional stenting has remained the preferred strategy for majority of bifurcation lesions, controversies still exist regarding when and how to use complex techniques. Most of randomised studies comparing simple and complex approaches have focused on selected populations, included both ‘true’ and ‘non-true’ bifurcation lesions, used first-generation drug eluting stents (DES) and favoured the crush technique performed in a suboptimal manner (i.e. no use of non-compliant balloon post-dilatation).1–3 Currently, there are increasingly more reasons to believe that optimally performed two-stent techniques, with the use of newgeneration DES, may provide similar or better results compared with the simple techniques.4–6 Studies have shown a trend towards improved clinical and/or angiographic outcomes with a two-stent strategy, when used in bifurcations with large side branches (SBs).7–10 Two of the studies also revealed that at follow-up, the SB diameter stenosis was higher, and restenosis was more frequent with provisional stenting.8,9 Moreover, these studies revealed that in true bifurcation lesions the rate of crossover from simple to complex strategies might be as high as 16 %.7 Furthermore, in an all-comers population of patients treated with current-generation DES, a provisional strategy bears a risk of intraprocedural SB closure exceeding 8 %.6

Limitations of Currently Used Stents Currently used stents were designed to treat lesions in simple anatomy of straight vessels, not at the bifurcation site, where often major stent deformations are necessary to adequately cover the target territory. This raises the following concerns: 1. Double-stent techniques are difficult, 1 more complex to perform than single-stent procedures, thus the outcomes are more operator dependent. 2. Stent distortion, which is common in complex techniques, may lead to strut fractures and malapposition, SB jailing or inability to fully cover the SB ostium.11,12

124

Access at: www.ICRjournal.com

ICR_Lesiak_FINAL2.indd 124

3. Most studies on currently used stents have revealed an increased risk of periprocedural MI with two-stent techniques,2,3 in comparison with simple procedures, while being equally effective, and safer than complex ones. These issues provide a potential role for dedicated bifurcation stents. These devices must be easy to use, effective in various lesion morphologies and safe.

Development of Dedicated Devices Currently, different dedicated devices are used or being developed and classified according to different rules. A simple classification is based on the primary role of the stent, i.e. main branch stents (MBS), dedicated to treating the main vessel; and side branch stents (SBS), dedicated to treating and protecting the SB. MBS allows for both simple and complex strategies, as needed. This group includes the following devices: Axxess™ (Biosensors Europe SA), BiOSS® and BiOSS LIM® (Balton), Nile CroCo® and Nile PAX® (Minvasys), STENTYS™ (STENTYS SAS), Xience SBA™ (Abbott Vascular), Twin Rail™ (Invatec/Medtronic), TAXUS® Petal™ (Boston Scientific) and others. Contrary to expectations, most are not easy to use, require wide operator experience, and may themselves cause some devicespecific technical problems. Therefore, many of these devices have not entered routine clinical practice. A guiding catheter larger than 6F is necessary to implant the Axxess, Xience SBA, and TAXUS Petal stents, wire wrapping may make implantation of some devices (e.g. Axxess, Nile CroCo, Twin Rail, Petal) demanding, device self-alignment is often incomplete (e.g. Xience SBA, TAXUS Petal), and active, controlled rotation may be impossible (e.g. Xience SBA).

Axxess Stent The Axxess stent is a 150 micron-thick strut, self-expanding nitinol stent, covered with Biolimus A9 ™ (Biosensors International), a drug released from biodegradable polymer. According to MADS (main, across, distal, side) classification, the stent belongs to the

07/10/2016 01:22

Dedicated Bifurcation Stents

M category (main proximal first), as it covers the only the proximal main branch (MB) up to the carina level.13 While recrossing into the SB is not necessary, this technique often requires additional implantation of one or two stents to treat the lesions located in distal MB and SB. The procedure itself requires experience and precision when nesting the device at the carina. In the AXXESS Plus pivotal study, device success rate was 93.5 %, and 80.9 % of the patients received additional stents.14 The overall rate of major adverse cardiac events (MACE) at 6 months was 11.2 %, with no cases of acute or subacute stent thrombosis (ST), although late ST was reported in 2.2 % of the treated patients. The recently published COBRA trial reported on 40 patients with true bifurcation lesions randomly assigned to treatment with the Axxess and additional BioMatrix™ (Biosensors International) stents or a culotte technique using XIENCE™ (Abbott Vascular).15 Implantation of the Axxess stent resulted in a significantly larger lumen in the proximal MB after the procedure and at follow-up, and in a lower angiographic late lumen loss (p=0.05). Both strategies resulted in good clinical outcomes with a rate of 10 % MACE at 1 year.

Figure 1: Bifurcation lesion stenting with a BiOSS ® stent A

A: Bifurcation lesion (arrow) of the circumflex artery (LCx). B: BiOSS® stent in position. Mid-marker at the carina level (arrowhead). C: Final result after stent implantation with no additional manoeuvres.

Figure 2: Bifurcation lesion stenting with a Tryton side branch stent A

BiOSS Stents The other device within MBS group is the BiOSS stent, for which there are two types: the older, paclitaxel-eluting BiOSS Expert® (Balton) and sirolimus-eluting BIOSS LIM. Both drugs are released from biodegradable polymer. The stent was designed to respect the fractal geometry of bifurcation, hence the proximal region has a larger diameter than the distal (the proximal/distal diameter ratio is 1.15–1.3). Both regions are joined by two connecting struts (mid zone). The stent is mounted on a special stepped delivery Bottle® balloon (Balton). The balloon mid marker, which shows the mid zone, allows for adequate stent positioning. According to the MADS classification,13 the stent belongs to ‘A’ group (provisional stenting). Once the mid marker is positioned at the tip of the carina, the stent is fully opened and no or minimal carina shift towards the SB should occur. An SB stent may by implanted as needed in either the T/T with protrusion or culotte mode.16 The ease of use is the major advantage of the BiOSS stent, whereas the lack of the coverage of the SB ostium is a major limitation. An example of bifurcation lesion stenting with a BiOSS stent is shown in Figure 1. In the POLBOS (Polish Bifurcation Optimal Stenting) I randomised study, the BiOSS Expert stent was compared with regular DES.17 A total of 243 patients were enrolled and randomised (1:1) to receive either treatment. Additional SB stenting was required in 10 % of cases in both groups. At 12 months, cumulative incidence of MACE was similar in both groups, but the target lesion revascularisation (TLR) rate was significantly higher in the BiOSS group (11.5 versus 7.3 %; p=0.02). In the POLBOS II study, patients were randomised to either the BiOSS LIM group (n=102) or to the conventional DES group (n=100).18 Contrary to expectations, SB stenting was required in a greater proportion of the BiOSS group (8.8 %) than the provisional group (7 %), but with no statistical significance. At 12 months, the cumulative incidences of MACE and TLR were similar in both groups: 11.8 versus 15 % (p=0.08) and 9.8 versus 9 % (p=0.8) for BiOSS LIM and DES groups, respectively. The BiOSS LIM stent was also examined in the prospective international registry enrolling 74 patients with distal left main stenosis.19 At 12 months, the rate of MACE was 9.5 % without cardiac death or definite stent thrombosis. TLR and MI rates were 6.8 % and 2.7 %, respectively.

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Lesiak_FINAL2.indd 125

DIA LAD

A: Critical bifurcation lesion (arrow) of the left anterior descending (LAD) and large diagonal artery (DIA). B: Tryton stent in position. Two mid-markers at the carina level (arrowheads). C: Tryton stent implantation. D: Main-vessel stent implantation. E: Final kissing inflation. F: High pressure post dilatation. G: Final result.

Advantage of Main Branch Stent-Dedicated Devices over Provisional Stenting with Conventional Drug-eluting Stents To date, no studies have shown a clear advantage of MBS-dedicated devices over provisional stenting with the use of conventional DES. Apart from the BiOSS stent, devices are not easy to use and require some extra device-specific skills. Another weakness of this technology is a limited range of device length, thus multiple stents may be required for implantation into the MB.

125

07/10/2016 01:22

Coronary The primary role of SBS devices is to treat and protect the SB during MB stenting. This allows for the use of any DES length and diameter to treat the main vessel lesion, both proximally and distally to the SB, which is an undisputable advantage of this approach. In contrast, the wide selection of DES covered with different polymers and drugs contributed to the current bare metal designs for SBS. This strategy a priori necessitates use of the two-stent technique, with one possible exemption of Medina 0,0,1 lesions.20 The Tryton SB stent (Tryton Medical) is the most widely studied dedicated device. This is a thin-strut, cobalt-chromium bare metal stent, and consists of three zones: a distal, slotted-tube SB zone, for treatment and protection of the SB; a transition zone, to be positioned at the SB ostium; and an MB zone with two wedding bands and three undulating fronds minimising the amount of metal. The stent is mounted either on a straight or on a stepped balloon, to respect the fractal geometry of coronary bifurcation. According to the MADS classification, the technique with the Tryton SB stent belongs to inverted ‘A’ category (inverted culotte). An example of bifurcation lesion stenting with a Tryton SB stent is shown in Figure 2. The stent has been examined in multiple registries and in one large randomised trial. In a large E-Tryton 150/Benelux registry a total of 302 patients were enrolled.21 Technical and procedural success rates reached 98.0 % and 94.4 %, respectively. The cumulative 6-month MACE rate was 6.4 % with no deaths, 4.7 % MI events, and 3.4 % target lesion revascularisation events. Only one case of stent thrombosis was reported. In the largest multicentre, randomised study to date, the TRYTON Pivotal Trial, the two-stent strategy with the use of Tryton SB stents in >700 patients with true bifurcation lesions, did not show clinical noninferiority to provisional main vessel stenting with regular DES, mainly due to a small excess of a study-defined periprocedural MI events.9 This could be explained by the inclusion of relatively small SBs in the trial. Actually, 60 % of patients did not meet the inclusion criterion of SB diameter >2.5 mm by visual estimate, which corresponded to the 2.25 mm determined in the quantitative coronary angiography (QCA) core laboratory analysis. A post-hoc analysis identified a strong interaction in the occurrence of the primary clinical endpoint (target vessel failure), showing lack of benefit of the complex strategy in smaller SBs and potential benefit in larger ones.10 This confirms the findings reported in recent randomised studies and registries with conventional stents implanted in bifurcation lesions with large SBs.6–8 Recently, the Tryton Confirmatory Study has been reported,22 a study designed to confirm the results of the post-hoc analysis of the TRYTON Pivotal trial. A total of 133 patients with bifurcation lesions containing large SBs (≥2.25 mm, confirmed by QCA) were enrolled. The primary endpoint was non-inferiority with regard to periprocedural MI as

Steigen TK, Maeng M, Wiseth R, et al. Randomized study on simple versus complex stenting of coronary artery bifurcation lesions: the Nordic bifurcation study. Circulation 2006;114 :1955–61. DOI: 10.1161/ CIRCULATIONAHA.106.664920; PMID: 17060387. Colombo A, Bramucci E, Saccà S, et al. Randomized study of the crush technique versus provisional side-branch stenting in true coronary bifurcations: the CACTUS (Coronary Bifurcations: Application of the Crushing Technique Using Sirolimus-Eluting Stents) Study. Circulation 2009;119 :71–8. DOI: 10.1161/CIRCULATIONAHA.108.808402; PMID: 19103990. Hildick-Smith D, de Belder AJ, Cooter N, et al. Randomized trial of simple versus complex drug-eluting stenting for bifurcation lesions: the British Bifurcation Coronary Study:

126

ICR_Lesiak_FINAL2.indd 126

compared with the provisional cohort of the previous Tryton study. In patients with large SBs, periprocedural MI rate (10.5 %) was lower than in the provisional group in the TRYTON Pivotal trial (11.9 %). This result has met the non-inferiority primary endpoint.22 Although no study revealed explicit superiority of the Tryton SB stent over a simple technique with current-generation DES, one should keep in mind that the stent is a bare metal device. Further improvement in clinical outcomes should be expected once the Tryton SB stent is designed to be covered with a potent antiproliferative drug.

Advances in Bifurcation Stenting Recently there have been major advances in bifurcation stenting. The widespread use of intravascular imaging, routine usage of the proximal optimisation technique and final kissing balloon inflations with noncompliant balloons improved markedly the clinical outcomes of percutaneous coronary intervention procedures. Bifurcation-dedicated technology needs much further improvement. Devices and techniques that require special operator skills or the use of unconventional accessories, will not likely be adopted. Simple, thin-strut, drug-eluting devices, with a high capacity for adaptation to various anatomical patterns will be eagerly accepted. Many interventional cardiologists instinctively feel that bifurcation-dedicated stents should finally overcome numerous limitations of conventional DES. However, none of the clinical studies reported thus far showed any advantage of this approach compared with simple provisional strategies. Perhaps the key is the proper selection of patients and lesions. Three anatomical factors seem to play a major role, and all involve an SB: the importance of this vessel, the extent of atherosclerotic disease and ease of SB access. The loss of a vessel supplying substantial amount of myocardium will always lead to a large periprocedural MI,23 which may worsen patients’ prognosis.24 Thus, it seems that the presence of a large SB, especially with significant stenosis at the ostium, should be an explicit indication for more complex techniques, with possible use of simple dedicated devices. Recent studies on systematic twostent strategies in large-calibre true bifurcations, with the use of current-generation conventional DES6–8 or dedicated stents9,10,19,22 seem to confirm this hypothesis. In addition, complexity of SB stenosis plays an important role. The authors of the Definitions and Impact of Complex Bifurcation Lesions on Clinical Outcomes After Percutaneous Coronary InterventIon Using Drug-eluting Stents (DEFINITION) study found that for complex bifurcation lesions with severe and extensive disease in the SB, two-stent techniques were associated with lower rates of in-hospital MACE and 1-year cardiac death as compared with provisional stenting.25

Conclusion While the provisional technique still remains a treatment of choice for bifurcation lesions, the use of complex two-stent strategy, with or without dedicated stents, may be a better option in cases in which an SB is large or diseased or if there is difficulty in accessing this vessel. n

old, new, and evolving strategies. Circulation 2010;121 : 1235–43. DOI: 10.1161/CIRCULATIONAHA.109.888297; PMID: 20194880. Chen SL, Santoso T, Zhang JJ, et al. A randomized clinical study comparing double kissing crush with provisional stenting for treatment of coronary bifurcation lesions: results from the DKCRUSH-II (Double Kissing Crush versus Provisional Stenting Technique for Treatment of Coronary Bifurcation Lesions) trial. J Am Coll Cardiol 2011;57 :914–20. DOI: 10.1016/j.jacc.2010.10.023; PMID: 21329837. Costopoulos C, Latib A, Ferrarello S, et al. First- versus second-generation drug-eluting stents for the treatment of coronary bifurcations. Cardiovasc Revasc Med 2013;14 :311–5. DOI: 10.1016/j.carrev.2013.09.006; PMID: 24157311.

Lee JM, Hahn JY, Kang J, et al. Differential Prognostic Effect Between First- and Second-Generation Drug-Eluting Stents in Coronary Bifurcation Lesions: Patient-Level Analysis of the Korean Bifurcation Pooled Cohorts. JACC Cardiovasc Interv 2015;8 :1318–31. DOI: 10.1016/j.jcin.2015.05.014; PMID: 26315734. Hildick-Smith D. A European bifurcation coronary study: a randomized comparison of provisional T-stenting versus a systematic 2-stent strategy in large caliber true bifurcations. Presented at: EuroPCR, Paris, France, 21 May 2015. Kumsars I. Randomized comparison of provisional sidebranch stenting versus a 2-stent strategy for treatment of true coronary bifurcation lesions involving a large side

INTERVENTIONAL CARDIOLOGY REVIEW

07/10/2016 01:22

Dedicated Bifurcation Stents

10.

11.

12.

13.

14.

branch. 2-year results in the Nordic-Baltic Bifurcation Study IV. Presented at: EuroPCR, Paris, France, 21 May 2015. Généreux P, Kumsars I Lesiak M. A randomized trial of a dedicated bifurcation stent versus provisional stenting in the treatment of coronary bifurcation lesions. J Am Coll Cardiol 2015;65 :533–43. DOI: 10.1016/j.jacc.2014.11.031; PMID: 25677311. Généreux P, Kini A, Lesiak M, et al. Outcomes of a dedicated stent in coronary bifurcations with large side branches: A subanalysis of the randomized TRYTON bifurcation study. Catheter Cardiovasc Interv 2016;87 :1231–41. DOI: 10.1002/ ccd.26240; PMID: 26397982. Ormiston JA, Webster MW, Ruygrok PN, et al. Stent deformation following simulated side-branch dilatation: a comparison of five stent designs. Catheter Cardiovasc Interv 1999;47 :258–64. DOI: 10.1002/(SICI)1522726X(199906)47:2<258::AID-CCD27>3.0.CO;2-C; PMID: 10376516. Ormiston JA, Currie E, Webster MW, et al. Drug-eluting stents for coronary bifurcations: insights into the crush technique. Catheter Cardiovasc Interv 2004;63 :332–6. DOI: 10.1002/ ccd.20120; PMID: 15505853. Louvard Y, Thomas M, Dzavik V, et al. Classification of coronary artery bifurcation lesions and treatments: time for a consensus! Catheter Cardiovasc Interv 2008;71 :175–83. DOI: 10.1002/ccd.21314; PMID: 17985377. Grube E, Buellesfeld L, Neumann FJ, et al. Six-month clinical and angiographic results of a dedicated drug-eluting stent for the treatment of coronary bifurcation narrowings. Am J Cardiol 2007;99 :1691–7. DOI: 10.1016/j. amjcard.2007.01.043; PMID: 17560877.

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Lesiak_FINAL2.indd 127

15. Dubois C, Bennett J, Dens J, et al. COmplex coronary Bifurcation lesions: RAndomized comparison of a strategy using a dedicated self-expanding biolimus-eluting stent versus a culotte strategy using everolimus-eluting stents: primary results of the COBRA trial. EuroIntervention 2016;11 :1457–67. DOI: 10.4244/EIJY15M05_02; PMID: 25947278. 16. Chan YH, Stella PR, Agostoni Pl. A “Simplified” culotte technique using two dedicated bifurcation stents and additional angiographic stent enhancement to treat a complex bifurcation lesion in non-ST segment elevation myocardial infarction with poor left ventricular function. Catheter Cardiovasc Interv 2015;85 :E163–5. DOI: 10.1002/ ccd.25795; PMID: 25534435. 17. Gil RJ, Bil J, Džavík V, et al. Regular Drug-Eluting Stent vs Dedicated Coronary Bifurcation BiOSS Expert Stent: Multicenter Open-Label Randomized Controlled POLBOS I Trial. Can J Cardiol 2015;31 :671–8. DOI: 10.1016/j.cjca. 2014.12.024; PMID: 25828372. 18. Gil RJ, Bil J, Grundeken MJ, et al. Regular drug-eluting stents versus the dedicated coronary bifurcation sirolimus-eluting BiOSS LIM® stent: the randomised, multicentre, open-label, controlled POLBOS II trial. EuroIntervention 2015;11 :pii: 20140419-05. DOI: 10.4244/EIJY15M11_11; PMID: 26600564. 19. Gil RJ, Bil J, Grundeken MJ, et al. Long-term effectiveness and safety of the sirolimus-eluting BiOSS LIM® dedicated bifurcation stent in the treatment of distal left main stenosis: an international registry. EuroIntervention 2015;11 :pii: 20150313-02. DOI: 10.4244/EIJY15M10_05; PMID: 26465375. 20. Grundeken MJ, Agostoni P, Lesiak M, et al. Placement of Tryton Side Branch Stent only; a new treatment strategy

21.

22.

23.

24.

25.

for Medina 0,0,1 coronary bifurcation lesions. Catheter Cardiovasc Interv 2013;82 :E395–402. DOI: 10.1002/ccd.24811; PMID: 23554121. Agostoni P, Foley D, Lesiak M, et al. A prospective multicentre registry, evaluating real-world usage of the Tryton side branch stent: results of the E-Tryton 150/Benelux registry. EuroIntervention 2012;7 :1293–300. DOI: 10.4244/ EIJV7I11A204; PMID: 22433192. Généreux P, Kumsars I, Schneider JE, et al. Dedicated Bifurcation Stent for the Treatment of Bifurcation Lesions Involving Large Side Branches. Outcomes From the Tryton Confirmatory Study. J Am Coll Cardiol Interv 2016;9 :1338–46. DOI: 10.1016/j.jcin.2016.03.042; PMID: 27388820. Kassab GS, Bhatt DL, Lefèvre T, Louvard Y. Relation of angiographic side branch calibre to myocardial mass: a proof of concept myocardial infarct index. EuroIntervention 2013;8 :1461–3. DOI: 10.4244/EIJV8I12A220; PMID: 23680961. Lindsey JB, Kennedy KF, Stolker JM, et al. Prognostic implications of creatine kinase-MB elevation after percutaneous coronary intervention: results from the Evaluation of Drug-Eluting Stents and Ischemic Events (EVENT) registry. Circ Cardiovasc Interv 2011;4 :474–80. DOI: 10.1161/CIRCINTERVENTIONS.111.962233; PMID: 21972402. Chen SL, Sheiban I, Xu B, Jepson N, et al. Impact of the complexity of bifurcation lesions treated with drug-eluting stents: the DEFINITION study (Definitions and impact of complEx biFurcation lesIons on clinical outcomes after percutaNeous coronary IntervenTIOn using drug-eluting steNts). JACC Cardiovasc Interv 2014;7 :1266–76. DOI: 10.1016/ j.jcin.2014.04.026; PMID: 25326748.

127

07/10/2016 01:22

Peripheral

Non-coronary Interventions: An Introduction to Peripheral Arterial Interventions Broc k C oo k m a n , S u h a i l A l l a q a b a n d a n d To n g a N f o r Aurora Cardiovascular Services, Aurora Sinai/Aurora St. Luke’s Medical Center, University of Wisconsin School of Medicine and Public Health, Milwaukee, Wisconsin, USA

Abstract With an ageing population, the burden of peripheral artery diseases (PADs) is increasing. The treatment of these diseases has largely been performed by interventional radiologists, vascular surgeons and interventional cardiologists. Due to the strong relationship between PAD and overall cardiovascular morbidity and mortality, cardiologists need to play a greater role in the management of PAD. The physician who cares for the patient with peripheral vascular disease should have a broad understanding of atherosclerotic disease involving all vascular beds. Endovascular interventions play a major role in relieving symptoms and reducing morbidity related to PAD, but long-term optimal medical treatment is an essential determinant of prognosis. This paper reviews current endovascular/percutaneous interventions for PAD.

Keywords Peripheral vascular interventions, endovascular aortic repair, infrapopliteal intervention, renal artery intervention, carotid artery intervention, mesenteric artery intervention, subclavian artery intervention, renal artery stenosis, carotid artery stenosis, mesenteric ischaemia, critical limb ischaemia Disclosure: The authors have no conflicts of interest to declare. Received: 16 February 2016 Accepted: 29 June 2016 Citation: Interventional Cardiology Review, 2016;11(2):128–34 DOI: 10.15420/icr.2016:8:2 Correspondence: Suhail Allaqaband, Aurora Cardiovascular Services, Aurora Sinai/Aurora St. Luke’s Medical Center, University of Wisconsin School of Medicine and Public Health, 2801 W. Kinnickinnic River Parkway, #840, Milwaukee, WI 53215, USA. E: publishing3@aurora.org

With an ageing population, the burden of peripheral artery diseases (PADs) is increasing. The treatment of these diseases has largely been performed by interventional radiologists, vascular surgeons and interventional cardiologists. In 2011, the percentage of procedures performed per specialty were 12.9 %, 45.0 % and 42.2 % for interventional radiology, vascular surgery and interventional cardiology, respectively.1 Due to the complexity of the disease and comorbidities of the patients with peripheral arterial disease, a multidisciplinary collaborative approach between these subspecialties is important for the best outcomes. Although there are rare atypical forms of PAD, it shares the same traditional risk factors for atherosclerotic disease; namely, smoking, diabetes mellitus, high blood pressure, dyslipidaemia and older age. Large registries have shown that 50–60 % of patients with PAD have cerebrovascular or coronary artery disease, and patients with PAD have a two-fold increase risk of all-cause mortality compared with those of matched Framingham risk scores with no PAD.2 The physician who cares for the patient with peripheral vascular disease should have a broad understanding of atherosclerotic disease involving all vascular beds. Although endovascular interventions play a major role in relieving symptoms and reducing the morbidity associated with PAD, longterm optimal medical treatment is an essential determinant of prognosis. The cornerstones to medical therapy are 3-hydroxy3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and antithrombotic therapy. Although randomised trial data are

128

Access at: www.ICRjournal.com

ICR_Allaqaband_FINAL2.indd 128

lacking with regard to the exact length of dual antiplatelet therapy with aspirin and clopidogrel, it does appear that short duration combination therapy is important following peripheral interventions. During the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, 15,603 patients were randomised to either clopidogrel plus low-dose aspirin or low-dose aspirin plus placebo. Dual antiplatelet therapy did not reduce the primary endpoints of death, myocardial infarction or cardiovascular death; however, it was associated with an increase in moderate bleeding.3 For iliac, femoropopliteal and drug-eluting stents, the current recommendations for dual antiplatelet therapy are 1 month, 1–3 months and 2 months, respectively.4 In situations such as stent graft repair, covered stents and poor outflow, long durations of dual antiplatelet therapy can be considered if the bleeding risk is low. This paper reviews current endovascular/percutaneous interventions for PAD.

Endovascular Aortic Repair Abdominal Aortic Aneurysm A ruptured aortic aneurysm carries a mortality rate >75 % and is the 13th leading cause of death in the USA.5 Routine screening is recommended in high-risk patients and repair should be considered when the aneurysm’s maximal diameter reaches 5.0–5.5 cm (varies by guidelines).6 Endovascular aneurysm repair (EVAR) using stent grafts is a popular treatment option for patients with abdominal aortic aneurysm. Due to favourable outcomes over open surgical repair, in

07/10/2016 01:27

Peripheral Arterial Interventions

current practice, endovascular repair accounts for more than 80 % of all cases of abdominal aortic aneurysm repair performed in the USA.7 Clinical trials comparing EVAR to open surgical repair demonstrate a significantly lower peri-procedural mortality and morbidity with EVAR but similar long-term mortality and a higher risk of repeat interventions due to graft endoleaks (see Table 1).8 EVAR is limited to the patients who meet the anatomic criteria for the stent graft device available. Most devices require an adequate proximal landing zone (aneurysm neck) that is 10–15 mm long and free of significant angulation or calcification. Newer devices have a smaller profile and a more flexible delivery system that are useful in patients with difficult iliac and common femoral anatomy. As an alternative to performing a femoral artery cutdown for vascular access, which requires surgical repair at the end of the procedure, many operators utilise the ’pre-close technique’9 for access site management, allowing for EVAR to be done entirely percutaneously. Figure 1 shows a computed tomography angiography (CTA) reconstruction of an infrarenal aortic aneurysm in a patient who presented for consideration of endovascular repair.

Table 1: Types of Endoleak After Aortic Aneurysm Repair Classification

Type of Endoleak

Type I

Proximal edge of the graft

Type II

Side-branch flow into the aneurysm

Type III

Graft failure or limb disconnection

Type IV

Leak through the graft itself

Type V

No detectable leak with aneurysm expansion

Source: Jackson RS et al., 2012.7

Figure 1: Computed Tomography Angiography Reconstruction of a 5.7-cm long Infrarenal Abdominal Aortic Aneurysm

Advanced techniques have been used for junta-renal aneurysms with poor landing zones that combine renal stenting with EVAR to maintain renal perfusion (see Figure 2).10 Fenestrated and branched grafts are also available to maintain renal and mesenteric perfusion in complex aneurysms, but their long-term outcomes remain to be demonstrated.

Descending Thoracic Aorta With current endovascular techniques and stent graft design, endovascular repair is the current treatment of choice for aneurysmal disease of the descending thoracic aorta that meet criteria for repair (see Figure 3).11 Contemporary trials comparing endovascular with surgical repair of descending thoracic aortic aneurysms have shown a significantly lower mortality (5.8 versus 13.9 %; p<0.001), stroke and paraplegia (8.9 versus 18.7 %; p<0.001), and other preoperative complications in patients treated with endovascular repair without increased risk of repeat interventions.12 With the improved outcomes seen with endovascular repair of the descending thoracic aortic aneurysms, this treatment has now been extended to Stanford type B acute aortic dissections. In the Investigation of Stent-grafts in Aortic Dissection (INSTEAD-XL) trial, endovascular repair was shown to improve aortic remodelling and decrease long-term vascular complications and mortality better than medical treatment alone in uncomplicated type B aortic dissections.13

The celiac, superior mesenteric and bilateral renal arteries are visualised and the patient was deemed appropriate for endovascular repair.

Figure 2: Examples of the Snorkel Technique

Lower Extremity Peripheral Arterial Disease The lower extremity is the most commonly affected arterial bed in patients with peripheral vascular disease. The Rutherford staging system (see Table 2) is used to classify the stages of lower extremity peripheral arterial disease. Categories 4, 5 and 6 constitute critical limb ischaemia. The goals of therapy for lower extremity arterial disease are to prevent cardiovascular morbidity and mortality, relieve symptoms and to preserve the limb. Medical therapy involves antiplatelet therapy with aspirin, Hmg-CoA reductase inhibitors, smoking cessation and control of diabetes and hypertension. Cilostazol may be added to reduce symptoms of intermittent claudication but its use is contraindicated in patients with congestive heart failure. A supervised walking exercise programme is recommended to promote collateral circulation and improve symptoms of claudication.

INTERVENTIONAL CARDIOLOGY REVIEW

ICR_Allaqaband_FINAL2.indd 129

(A) Abdominal aortic angiography performed showing the presence of a juxtarenal abdominal aortic aneurysm with an aneurysmal neck involving the bilateral renal arteries, undeployed stents placed in the renal arteries; (B) Successful aneurysm exclusion using a Medtronic Endograft with bilateral renal artery stenting to maintain patency of the renal arteries.

Revascularisation is recommended in patients with significant claudication refractory to medical therapy, critical limb ischaemia (rest pain, non-healing ulcer or gangrene) or acute limb ischaemia. The choice of revascularisation strategy is largely based on the likelihood of technical success and long-term vessel patency. The Trans-Atlantic

129

07/10/2016 01:27

Peripheral Figure 3: Example of Thoracic Aortic Arch Aneurysm Deemed High Surgical Risk

Angiography (A) following right-to-left subclavian and left carotid artery bypass prior to endograft repair; (B) of the aortic arch after exclusion of the aneurysmal segment with a Medtronic endograft. The left subclavian and carotid arteries occluded at the origin from the aortic arch by the endograft are now filled via right-to-left bypass or debranching.

Table 2: Rutherford Staging of Lower Extremity Peripheral Arterial Disease Grade